JP6234446B2 - Fusion polypeptide comprising an active protein linked to a mucin domain polypeptide - Google Patents
Fusion polypeptide comprising an active protein linked to a mucin domain polypeptide Download PDFInfo
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- JP6234446B2 JP6234446B2 JP2015516220A JP2015516220A JP6234446B2 JP 6234446 B2 JP6234446 B2 JP 6234446B2 JP 2015516220 A JP2015516220 A JP 2015516220A JP 2015516220 A JP2015516220 A JP 2015516220A JP 6234446 B2 JP6234446 B2 JP 6234446B2
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Description
関連出願(複数可)
本出願は、2012年6月8日に出願された米国仮出願第61/657,264号、2013年3月13日に出願された同第61/778,575号、2012年6月8日に出願された同第61/657,378号、2012年11月6日に出願された同第61/723,081号、2012年6月8日に出願された同第61/657,285号、および2013年3月13日に出願された同第61/778,812号の利益を請求するものである。上記の出願(複数可)の全教示は、参照により本明細書に援用される。
Related application (s)
This application is based on US Provisional Application No. 61 / 657,264, filed June 8, 2012, 61 / 778,575, filed March 13, 2013, June 8, 2012. No. 61 / 657,378 filed on Nov. 6, 2012, No. 61 / 723,081 filed Nov. 6, 2012, No. 61 / 657,285 filed Jun. 8, 2012 , And the benefit of 61 / 778,812, filed March 13, 2013. The entire teachings of the above application (s) are incorporated herein by reference.
配列表
本出願は、EFS−Web経由でASCII形式により提出された配列表を含み、この配列表は参照によりその全体が本明細書に援用される。2013年5月31日に作成された前記ASCIIコピーは、4000.3058WO_SL.txtという名前であり、サイズは27,431バイトである。
SEQUENCE LISTING This application contains a Sequence Listing submitted in ASCII format via EFS-Web, which is incorporated herein by reference in its entirety. The ASCII copy created on May 31, 2013 is named 4000.3058WO_SL.txt and has a size of 27,431 bytes.
タンパク質治療薬の薬物動態、薬物分布(pharmacodistribution)、溶解性、安定性、エフェクター機能および受容体結合の増強は、グリコシル化タンパク質の炭水化物部分が著しく影響を与え得る。さらに、多くの生物活性のあるペプチドおよびタンパク質は、溶解性が限られているか、または組換え生成中に凝集し、複雑な可溶化手順およびリフォールディング手順を必要とする。さらに、60キロダルトン(kD)より低い分子量を有するタンパク質およびペプチド治療薬は、腎クリアランスにより半減期が短いことが悩みの種である場合が多い。 The pharmacokinetics, pharmacodistribution, solubility, stability, effector function and enhancement of receptor binding of protein therapeutics can be significantly influenced by the carbohydrate portion of glycosylated proteins. In addition, many biologically active peptides and proteins have limited solubility or aggregate during recombinant production, requiring complex solubilization and refolding procedures. In addition, protein and peptide therapeutics with molecular weights lower than 60 kilodaltons (kD) are often annoying due to their short half-life due to renal clearance.
タンパク質治療薬の血中半減期を延長するために用いられている現在の戦略は、主に2つの一般的なカテゴリー:1)FcRn媒介性リサイクルの利用、および2)流体力学容積の増加に入る。説明されている具体的なアプローチには、前者の戦略についてはFcRn結合タンパク質もしくはドメイン(Fc、アルブミン)へのコンジュゲーション、結合、または融合が含まれ、後者については多量体化、(PEG、コロミン酸、またはヒドロキシエチルデンプンなどの)ポリマーまたは炭水化物への化学的結合、Nグリコシル化部位の組み込みが含まれる。しかし、Fc融合タンパク質の生成は、追加の製造ステップ、および多くの場合、複雑な精製手順を必要とする、時間がかかり、非効率的でお金のかかるプロセスである。さらに、最も広く使用されている化学的カップリング戦略のPEG化が、コンジュゲーションおよび精製ステップの追加ならびに全体的な収率の低下により製造コストの著しい増加をもたらす。近年、米国特許公開2010/0239554に記載されているものなどの、柔軟な長いポリペプチド配列の融合により産生される他の組換えPEG模倣物についても説明されている。この技術は、追加のコンジュゲーションステップを回避するが、非内因性の追加のペプチド配列は免疫原性の可能性を有する。 Current strategies used to extend the blood half-life of protein therapeutics mainly fall into two general categories: 1) use of FcRn-mediated recycling, and 2) increase in hydrodynamic volume . Specific approaches that have been described include conjugation, binding, or fusion to FcRn binding proteins or domains (Fc, albumin) for the former strategy, multimerization for the latter (PEG, colomine) Includes chemical conjugation to polymers or carbohydrates (such as acids or hydroxyethyl starch), incorporation of N-glycosylation sites. However, the production of Fc fusion proteins is a time consuming, inefficient and expensive process that requires additional manufacturing steps and often complicated purification procedures. Furthermore, PEGylation of the most widely used chemical coupling strategy results in a significant increase in manufacturing costs due to the addition of conjugation and purification steps and a reduction in overall yield. Recently, other recombinant PEG mimetics produced by fusion of flexible long polypeptide sequences, such as those described in US Patent Publication 2010/0239554, have also been described. This technique avoids additional conjugation steps, but non-endogenous additional peptide sequences have the potential for immunogenicity.
ムチンタンパク質およびタンパク質のムチンドメインは、ムチンタンパク質およびムチンドメインを含む他のポリペプチドが硬直したランダムコイルとして動作することを構造的に可能にする高度のグリコシル化を含む。高度にグリコシル化されたムチンドメインを構成する親水性の分枝状親水性炭水化物と組み合わせた、この硬直したランダムコイル状構造は、活性タンパク質の流体力学半径を、発現タンパク質の分子量に基づいて予想される半径よりも大きくさせるのに特に有用である。また、高レベルのグリコシル化にとって、ムチンドメインの付加は、活性タンパク質の電荷、溶解性および濃縮溶液の粘弾性特性などのタンパク質の物理化学的特性を変更する可能性も有する。 Mucin proteins and mucin domains of proteins contain a high degree of glycosylation that structurally allows mucin proteins and other polypeptides containing mucin domains to act as rigid random coils. This rigid random coiled structure, combined with the hydrophilic branched hydrophilic carbohydrates that make up the highly glycosylated mucin domain, predicts the hydrodynamic radius of the active protein based on the molecular weight of the expressed protein It is particularly useful for making it larger than the radius. Also for high levels of glycosylation, the addition of mucin domains has the potential to alter the physicochemical properties of the protein, such as the charge, solubility and viscoelastic properties of the concentrated solution of the active protein.
本発明の融合タンパク質組成物および方法は、活性タンパク質の生物学的特性、薬理学的特性、安全性特性、および/または薬学的特性を向上させる。 The fusion protein compositions and methods of the present invention improve the biological, pharmacological, safety, and / or pharmaceutical properties of the active protein.
本発明は、ムチンドメインポリペプチドと共有結合していない同じ活性タンパク質と比較して、特性(例えば、薬物動態学的および/または物理化学的特性)が向上した活性タンパク質と共有結合したムチンドメインポリペプチドを含む融合タンパク質、ならびに本発明の融合タンパク質の作製法および使用法を提供する。 The present invention relates to mucin domain polypeptides covalently linked to an active protein with improved properties (eg, pharmacokinetic and / or physicochemical properties) compared to the same active protein that is not covalently linked to a mucin domain polypeptide. Fusion proteins comprising peptides and methods for making and using the fusion proteins of the invention are provided.
一実施形態において、本発明は、ムチンドメインポリペプチドに融合されていない対応する活性タンパク質と比較して、活性タンパク質の少なくとも1つの薬物動態学的または物理化学的特性が向上している活性タンパク質に結合したムチンドメインポリペプチドを含む融合タンパク質を提供する。 In one embodiment, the present invention provides an active protein that has improved at least one pharmacokinetic or physicochemical property of the active protein compared to a corresponding active protein that is not fused to a mucin domain polypeptide. Fusion proteins comprising linked mucin domain polypeptides are provided.
一実施形態において、本発明は、本発明の融合タンパク質をコードする核酸配列、ならびに本発明の核酸を発現するためのベクターおよび宿主細胞を提供する。 In one embodiment, the invention provides a nucleic acid sequence encoding a fusion protein of the invention, as well as vectors and host cells for expressing the nucleic acids of the invention.
一実施形態において、本発明は、治療活性タンパク質の血清半減期を延長するための方法を提供する。 In one embodiment, the present invention provides a method for extending the serum half-life of a therapeutically active protein.
一実施形態において、本発明は、治療活性タンパク質の溶解性の向上を提供する。 In one embodiment, the present invention provides improved solubility of therapeutically active proteins.
一実施形態において、本発明は、本発明の融合タンパク質を含む医薬組成物を提供する。 In one embodiment, the present invention provides a pharmaceutical composition comprising the fusion protein of the present invention.
一実施形態において、本発明は、本発明の医薬組成物を用いた治療を必要とする対象における疾患、病状および障害を治療する方法を提供する。 In one embodiment, the present invention provides a method of treating diseases, conditions and disorders in a subject in need of treatment with a pharmaceutical composition of the present invention.
本発明の好ましい実施形態を以下に説明する。 Preferred embodiments of the present invention are described below.
定義
本明細書で使用する以下の用語は、特に断りのない限り、それらに帰する意味を有する。
Definitions As used herein, the following terms have the meanings ascribed to them unless specified otherwise.
本明細書および特許請求の範囲で使用する単数形「1つ(a」」、「1つ(an)」および「その」は、文脈が特に明確に指示しない限り、複数の言及を含む。例えば、「細胞」という用語は、その混合物を含む複数の細胞を含む。 As used herein and in the claims, the singular forms “a”, “an”, and “an” include plural references unless the context clearly dictates otherwise. The term “cell” includes a plurality of cells, including mixtures thereof.
「ポリペプチド」、「ペプチド」、および「タンパク質」という用語は、任意の長さのアミノ酸のポリマーを指すために本明細書において互換的に使用される。ポリマーは直鎖状でも分岐状でもよく、修飾アミノ酸を含んでもよく、非アミノ酸によって中断されていてもよい。この用語はまた、例えば、ジスルフィド結合形成、グリコシル化、脂質化、アセチル化、リン酸化、または標識成分とのコンジュゲーションなどの任意の他の操作によって修飾されたアミノ酸ポリマーも包含する。 The terms “polypeptide”, “peptide”, and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. The term also encompasses amino acid polymers that have been modified by any other manipulation, such as, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or conjugation with a labeling component.
本明細書で使用する「アミノ酸」という用語は、グリシンおよびDもしくはLの両方の光学異性体、アミノ酸類似体ならびにペプチド模倣体を含むがこれらに限定されない天然および/もしくは非天然アミノ酸または合成アミノ酸のいずれかを指す。標準的な単一文字または3文字コードを用いて、アミノ酸を指定する。 As used herein, the term “amino acid” refers to natural and / or unnatural amino acids or synthetic amino acids, including but not limited to optical isomers, amino acid analogs and peptidomimetics of both glycine and D or L. Point to either. Amino acids are designated using standard single letter or three letter codes.
配列に適用され、本明細書で用いられる「非天然」という用語は、哺乳類にみられる野生型もしくは天然の配列に対する対応物を有していないか、相補的ではないか、または高度の相同性を有していないポリペプチドもしくはポリヌクレオチド配列を意味する。例えば、非天然ポリペプチドは、適切に整列させた場合、天然配列と比較して99%、98%、95%、90%、80%、70%、60%、50%またはそれ以下のアミノ酸配列同一性を共有していてよい。 The term “non-natural” as applied to a sequence and as used herein, has no counterpart, is not complementary, or has a high degree of homology to the wild-type or natural sequence found in mammals. Means a polypeptide or polynucleotide sequence that does not have For example, a non-natural polypeptide, when properly aligned, has a 99%, 98%, 95%, 90%, 80%, 70%, 60%, 50% or less amino acid sequence compared to the native sequence. You may share identity.
「グリコシル化」および「グリコシル化された」という用語は、細胞内での生成中に、タンパク質の炭水化物部分、または糖が翻訳後にタンパク質に結合して糖タンパク質を形成するプロセスを意味するために本明細書で交換的に使用される。タンパク質のグリコシル化は、翻訳後事象であり、セリンおよびスレオニンへのグリカンの結合、ならびに程度は低いがO−結合型グリコシル化の場合にはヒドロキシプロリンおよびヒドロキシリジンへのグリカンの結合、またはN−結合型グリコシル化の場合にはアスパラギンへのグリカンの結合を指す。 The terms “glycosylated” and “glycosylated” are intended to mean the carbohydrate part of a protein, or the process by which sugars are post-translationally bound to proteins to form glycoproteins during production in the cell. Used interchangeably in the specification. Protein glycosylation is a post-translational event, glycan binding to serine and threonine, and to a lesser extent O-linked glycosylation, glycan binding to hydroxyproline and hydroxylysine, or N- In the case of linked glycosylation, it refers to the binding of a glycan to asparagine.
「断片」とは、治療活性および/または生物活性の少なくとも一部を保持する天然の活性タンパク質の切断型である。「変異体」は、活性タンパク質の治療活性および/または生物活性の少なくとも一部を保持する天然の活性タンパク質と配列相同性を有するタンパク質である。例えば、変異体タンパク質は、参照活性タンパク質と少なくとも70%、75%、80%、85%、90%、95%、96%、97%、98%または99%のアミノ酸配列同一性を共有してよい。本明細書で使用する「活性タンパク質部分」という用語は、例えば、部位特異的変異誘発により、挿入により、または偶然の変異を介して意図的に修飾されたタンパク質を含む。 A “fragment” is a truncated form of a naturally-occurring active protein that retains at least a portion of therapeutic and / or biological activity. A “variant” is a protein having sequence homology with a naturally occurring active protein that retains at least part of the therapeutic and / or biological activity of the active protein. For example, a variant protein shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity with a reference active protein. Good. As used herein, the term “active protein moiety” includes proteins that have been intentionally modified, eg, by site-directed mutagenesis, by insertion, or through accidental mutation.
「宿主細胞」は、対象ベクターのレシピエントであり得るか、またはそうであった個々の細胞もしくは細胞培養物を含む。宿主細胞は、単一の宿主細胞の子孫を含む。子孫は、天然、偶発的、または意図的な変異により、(形態または全DNA相補体のゲノムにおいて)元の親細胞と必ずしも完全に同一でなくてよい。宿主細胞は、本発明のベクターでインビボトランスフェクトされた細胞を含む。 A “host cell” includes an individual cell or cell culture that can be or has been a recipient of a subject vector. A host cell includes the progeny of a single host cell. The progeny may not necessarily be completely identical to the original parent cell (in the form or in the genome of the total DNA complement) due to natural, accidental or intentional mutation. Host cells include cells that have been transfected in vivo with a vector of the invention.
本明細書に開示される様々なポリペプチドを記載するために使用される場合に、「単離された」とは、その自然環境の成分から特定および分離ならびに/または回収されたポリペプチドを意味する。その自然環境の汚染成分は、典型的には、ポリペプチドの診断または治療上の使用を妨げる物質であり、酵素、ホルモン、および他のタンパク質性または非タンパク質性の溶質を含んでいてもよい。当業者には明らかなように、非天然のポリヌクレオチド、ペプチド、ポリペプチド、タンパク質、抗体、またはその断片は、その天然の対応物から区別するために「単離」を必要としない。さらに、「濃縮」、「分離」または「希釈」されたポリヌクレオチド、ペプチド、ポリペプチド、タンパク質、抗体、またはその断片は、容積あたりの分子の濃度または数が、一般的にその天然の対応物の容積あたりの分子の濃度または数より大きいという点で、その天然の対応物から区別可能である。一般的に、組換え手段により作製され、宿主細胞内で発現したポリペプチドは、「単離された」と考えられる。 As used to describe the various polypeptides disclosed herein, “isolated” means a polypeptide that has been identified and separated and / or recovered from a component of its natural environment. To do. Contaminating components of its natural environment are typically substances that interfere with the diagnostic or therapeutic use of the polypeptide and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. As will be apparent to those skilled in the art, a non-natural polynucleotide, peptide, polypeptide, protein, antibody, or fragment thereof does not require “isolation” to distinguish it from its natural counterpart. In addition, a “concentrated”, “separated” or “diluted” polynucleotide, peptide, polypeptide, protein, antibody, or fragment thereof has a concentration or number of molecules per volume, generally its natural counterpart Is distinguishable from its natural counterpart in that it is greater than the concentration or number of molecules per volume. In general, a polypeptide produced by recombinant means and expressed in a host cell is considered “isolated”.
「単離された」ポリヌクレオチドもしくはポリペプチドをコードする核酸または他のポリペプチドをコードする核酸は、ポリペプチドがコードする核酸の天然源に通常付随する少なくとも1種類の混入核酸分子から特定および分離される核酸分子である。単離されたポリペプチドをコードする核酸分子は、自然界で見られる形態または設定では存在しない。したがって、単離されたポリペプチドをコードする核酸分子は、天然の細胞中に存在するような特定のポリペプチドをコードする核酸分子とは区別される。しかし、単離されたポリペプチドをコードする核酸分子は、例えば、その核酸分子が天然細胞のものとは異なる染色体または染色体外の位置にあり、通常そのポリペプチドを発現する細胞に含まれるポリペプチドをコードする核酸分子を含む。 Nucleic acids encoding "isolated" polynucleotides or polypeptides or nucleic acids encoding other polypeptides are identified and separated from at least one contaminating nucleic acid molecule normally associated with the natural source of the nucleic acid encoded by the polypeptide. Nucleic acid molecule. A nucleic acid molecule encoding an isolated polypeptide does not exist in the form or setting found in nature. Thus, a nucleic acid molecule that encodes an isolated polypeptide is distinguished from a nucleic acid molecule that encodes a specific polypeptide as it exists in natural cells. However, a nucleic acid molecule that encodes an isolated polypeptide is, for example, a polypeptide that is contained in a cell in which the nucleic acid molecule is located in a chromosome or extrachromosomal location different from that of natural cells and usually expresses the polypeptide. A nucleic acid molecule encoding.
「コンジュゲートされる」、「連結される」、「融合される」および「融合」は、本明細書中で交換的に使用される。これらの用語は、化学的コンジュゲーションまたは組換え手段を含む何らかの手段によって2種類以上の化学的要素または成分が結合することを指す。例えば、プロモーターまたはエンハンサーは、配列の転写に影響を及ぼす場合に、コード配列に作動可能に連結される。一般的に、「作動可能に連結される」とは、連結されるDNA配列が読み枠(reading phase)中またはインフレームで近接することを意味する。「インフレーム融合」は、元のORFの正しいリーディングフレームを維持する方法で、連続的なより長いORFを形成するための、2種類以上のオープンリーディングフレーム(ORF)の結合を指す。したがって、得られる組換え融合タンパク質は、元のORFによってコードされるポリペプチドに対応する2種類以上のセグメント(これらのセグメントは通常、自然界ではそのように結合していない)を含む単一タンパク質である。 “Conjugated”, “linked”, “fused” and “fusion” are used interchangeably herein. These terms refer to the joining of two or more chemical elements or components by any means including chemical conjugation or recombinant means. For example, a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence. In general, “operably linked” means that the DNA sequences to be linked are in close proximity in the reading phase or in frame. “In-frame fusion” refers to the joining of two or more open reading frames (ORFs) to form a continuous longer ORF in a manner that maintains the correct reading frame of the original ORF. Thus, the resulting recombinant fusion protein is a single protein comprising two or more types of segments corresponding to the polypeptide encoded by the original ORF (these segments are usually not so associated in nature). is there.
ポリペプチドの文脈において、「直鎖状配列」または「配列」は、配列中で互いに隣接する残基がポリペプチドの一次構造において近接している、アミノ末端からカルボキシル末端方向へのポリペプチド中のアミノ酸の順番である。「部分配列」は、一方向または両方向に追加残基を含むことが知られているポリペプチド部分の直鎖状配列である。 In the context of a polypeptide, a “linear sequence” or “sequence” is a term in a polypeptide from the amino terminus to the carboxyl terminus in which the residues adjacent to each other in the sequence are close in the primary structure of the polypeptide. The order of amino acids. A “partial sequence” is a linear sequence of polypeptide portions known to contain additional residues in one or both directions.
「異種」とは、比較されている実体の残りとは遺伝子型が異なる実体に由来することを意味する。例えば、その天然のコード配列から取り出され、天然配列以外のコード配列に作動可能に連結されたグリシンリッチ配列は、異種グリシンリッチ配列である。ポリヌクレオチド、ポリペプチドに適用される「異種」という用語は、ポリヌクレオチドまたはポリペプチドが、比較されている実体の残りのそれとは遺伝子型が異なる実体に由来することを意味する。 “Heterologous” means derived from an entity whose genotype differs from the rest of the entity being compared. For example, a glycine rich sequence that is removed from its native coding sequence and operably linked to a coding sequence other than the native sequence is a heterologous glycine rich sequence. The term “heterologous” as applied to a polynucleotide, polypeptide means that the polynucleotide or polypeptide is derived from an entity that is genotyped different from that of the rest of the entity being compared.
「ポリヌクレオチド」、「核酸」、「ヌクレオチド」および「オリゴヌクレオチド」という用語は、互換的に使用される。これらは、デオキシリボヌクレオチドまたはリボヌクレオチドのいずれかの任意の長さのヌクレオチド、またはそのアナログのポリマー形態を指す。ポリヌクレオチドは、既知または未知の任意の三次元構造を有することができ、既知または未知の任意の機能を実行することができる。以下のものは、ポリヌクレオチドの非限定的な例である:遺伝子または遺伝子断片のコード領域または非コード領域、連鎖解析から定義される遺伝子座(複数可)、エクソン、イントロン、メッセンジャーRNA(mRNA)、トランスファーRNA、リボソームRNA、リボザイム、cDNA、組換えポリヌクレオチド、分枝ポリヌクレオチド、プラスミド、ベクター、任意の配列の単離DNA、任意の配列の単離RNA、核酸プローブ、およびプライマー。ポリヌクレオチドは、メチル化ヌクレオチドおよびヌクレオチドアナログなどの修飾されたヌクレオチドを含むことができる。存在する場合には、ヌクレオチド構造への修飾は、ポリマーのアセンブリの前後に付与され得る。ヌクレオチドの配列は、非ヌクレオチド成分により中断されてもよい。 The terms “polynucleotide”, “nucleic acid”, “nucleotide” and “oligonucleotide” are used interchangeably. These refer to polymeric forms of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. A polynucleotide can have any known or unknown three-dimensional structure and can perform any known or unknown function. The following are non-limiting examples of polynucleotides: coding region or non-coding region of a gene or gene fragment, locus (s) defined from linkage analysis, exon, intron, messenger RNA (mRNA) Transfer RNA, ribosomal RNA, ribozyme, cDNA, recombinant polynucleotide, branched polynucleotide, plasmid, vector, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probe, and primer. A polynucleotide can comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components.
ポリヌクレオチドに適用される「組換え」は、ポリヌクレオチドが、潜在的に宿主細胞内で発現させることができるコンストラクトをもたらすインビトロクローニング、制限酵素切断および/またはライゲーションのステップ、ならびに他の手順の様々な組合せの産物であることを意味する。 “Recombinant” as applied to a polynucleotide refers to a variety of in vitro cloning, restriction enzyme cleavage and / or ligation steps, and other procedures that result in a construct that the polynucleotide can potentially be expressed in a host cell. Is a product of a simple combination.
「遺伝子」または「遺伝子断片」という用語は、本明細書で互換的に使用される。これらは、転写および翻訳された後に特定のタンパク質をコードすることができる少なくとも1つのオープンリーディングフレームを含むポリヌクレオチドを指す。遺伝子または遺伝子断片は、ポリヌクレオチドが少なくとも1種類のオープンリーディングフレームを含む限り、全コード領域またはそのセグメントをカバーすることができるゲノムまたはcDNAであり得る。「融合遺伝子」は、共に連結された少なくとも2種類の異種ポリヌクレオチドで構成される遺伝子である。 The terms “gene” or “gene fragment” are used interchangeably herein. These refer to polynucleotides that include at least one open reading frame that can be encoded for a particular protein after being transcribed and translated. A gene or gene fragment can be a genome or cDNA that can cover the entire coding region or a segment thereof as long as the polynucleotide contains at least one open reading frame. A “fusion gene” is a gene composed of at least two heterologous polynucleotides linked together.
「相同性」または「相同」は、2種類以上のポリヌクレオチド配列または2種類以上のポリペプチド配列間の配列の類似性または互換性を指す。2種類の異なるアミノ酸配列間の配列同一性、類似性または相同性を決定するためにベストフィット(BestFit)などのプログラムを使用する場合、デフォルト設定を使用するか、またはblosum45またはblosum80などの適切なスコアリングマトリックスを選択して、同一性、類似性または相同性のスコアを最適化することができる。好ましくは、相同なポリヌクレオチドは、本明細書で定義されるストリンジェントな条件下でハイブリダイズし、それらの配列に対して少なくとも70%、好ましくは少なくとも80%、より好ましくは少なくとも90%、より好ましくは95%、より好ましくは97%、より好ましくは98%、さらにより好ましくは99%の配列同一性を有する。 “Homology” or “homology” refers to sequence similarity or interchangeability between two or more polynucleotide sequences or two or more polypeptide sequences. When using a program such as BestFit to determine sequence identity, similarity or homology between two different amino acid sequences, use the default settings or an appropriate such as blossum 45 or blossum 80 A scoring matrix can be selected to optimize the score for identity, similarity or homology. Preferably, homologous polynucleotides hybridize under stringent conditions as defined herein and are at least 70%, preferably at least 80%, more preferably at least 90%, more than their sequence. Preferably it has 95%, more preferably 97%, more preferably 98%, even more preferably 99% sequence identity.
「ストリンジェントな条件」または「ストリンジェントなハイブリダイゼーション条件」という用語は、ポリヌクレオチドが、他の配列よりも検出可能な高い割合(例えば、バックグラウンドの少なくとも2倍)でその標的配列にハイブリダイズする条件への言及を含む。一般的に、ハイブリダイゼーションのストリンジェンシーは、ある程度、洗浄ステップが実施される温度および塩濃度に関連して表される。典型的には、ストリンジェントな条件は、塩濃度がpH7.0〜8.3で約1.5M未満のNaイオンであり、典型的には約0.01〜1.0MのNaイオン(または他の塩)濃度であり、短いポリヌクレオチド(例えば、10〜50ヌクレオチド)についての温度は少なくとも約30℃であり、(例えば、50ヌクレオチドより大きい)長いポリヌクレオチドについての温度は少なくとも約60℃である。例えば、「ストリンジェントな条件」は、37℃で50%ホルムアミド、1MのNaCl、1%SDS中でのハイブリダイゼーション、およびそれぞれ60〜65℃での0.1×SSC/1%SDSにおける15分間の3回の洗浄を含み得る。あるいは、約65℃、60℃、55℃、または42℃の温度を使用してもよい。SDSは約0.1%で存在し、SSC濃度は、約0.1〜2×SSCと変化してもよい。このような洗浄温度は、典型的には、規定のイオン強度およびpHにおける特定配列の熱融点よりも約5℃〜20℃低いように選択される。Tmは、標的配列の50%が完全にマッチしたプローブにハイブリダイズする(規定のイオン強度およびpH下での)温度である。核酸ハイブリダイゼーションのためのTmおよび条件を計算するための式は、公知であり、Sambrook、J.et al. (1989) Molecular Cloning:A Laboratory Manual, 2nd ed., Vol 1−3, Cold Spring Harbor Press, Plainview N.Y.; で見つけることができ、特に、Colume そして Chapter 9を参照されたい。典型的には、ブロッキング試薬を用いて、非特異的なハイブリダイゼーションを阻止する。このようなブロッキング試薬は、例えば、剪断および変性されたサケ精子DNAを約100〜200μg/mlで含む。約35〜50%v/vの濃度のホルムアミドなどの有機溶媒も、RNA:DNAハイブリダイゼーションなどのための特定の条件下で使用してもよい。これらの洗浄条件に有用なバリエーションは、当業者には容易に明らかであろう。
The terms “stringent conditions” or “stringent hybridization conditions” refer to polynucleotides that hybridize to their target sequence at a higher rate (eg, at least twice background) than other sequences. Includes a reference to the conditions to do. In general, the stringency of hybridization is expressed to some extent in relation to the temperature and salt concentration at which the wash step is performed. Typically, stringent conditions are Na ions with a salt concentration of pH 7.0-8.3 and less than about 1.5M, typically about 0.01-1.0M Na ions (or Other salt) concentrations, the temperature for short polynucleotides (eg, 10-50 nucleotides) is at least about 30 ° C., and the temperature for long polynucleotides (eg, greater than 50 nucleotides) is at least about 60 ° C. is there. For example, “stringent conditions” are: hybridization in 50% formamide, 1M NaCl, 1% SDS at 37 ° C., and 0.1 × SSC / 1% SDS for 15 minutes at 60-65 ° C., respectively. 3 washings. Alternatively, temperatures of about 65 ° C., 60 ° C., 55 ° C., or 42 ° C. may be used. SDS is present at about 0.1%, and the SSC concentration may vary from about 0.1 to 2 × SSC. Such a washing temperature is typically selected to be about 5 ° C. to 20 ° C. below the thermal melting point of the specific sequence at a defined ionic strength and pH. Tm is the temperature (under defined ionic strength and pH) at which 50% of the target sequence hybridizes to a perfectly matched probe. The equations for calculating Tm and conditions for nucleic acid hybridization are known and are described in Sambrook, J. et al. (1989) Molecular Cloning: A Laboratory Manual, 2nd ed. , Vol 1-3, Cold Spring Harbor Press, Plainview N .; Y. See in particular Colume and
ポリヌクレオチド配列に適用される「パーセント同一性」および「%同一性」という用語は、標準化されたアルゴリズムを使用して整列される少なくとも2種類のポリヌクレオチド配列間の残基の一致の割合を指す。このようなアルゴリズムは、標準化され、再現性のある方法で、2種類の配列間のアラインメントを最適化するために比較される配列中にギャップを挿入し、それによって、2種類の配列のより有意義な比較を達成することができる。パーセント同一性は、例えば、特定の配列番号によって定義されるような所与のポリヌクレオチド配列の全長にわたって測定されるか、またはより短い長さにわたって、例えば、より長い所与のポリヌクレオチド配列から取得される断片、例えば、少なくとも45、少なくとも60、少なくとも90、少なくとも120、少なくとも150、少なくとも210または少なくとも450個の連続残基の断片の長さにわたって測定されてもよい。このような長さは単なる例示であり、本明細書、表、図、または配列表に示される配列によって支持される任意の断片長を用いて、パーセント同一性を測定することができる長さについて説明してもよいことが理解される。 The terms “percent identity” and “% identity” as applied to a polynucleotide sequence refer to the percentage of residue matches between at least two polynucleotide sequences that are aligned using a standardized algorithm. . Such an algorithm inserts gaps in the sequences that are compared to optimize the alignment between the two sequences in a standardized and reproducible manner, thereby making the two sequences more meaningful. Comparison can be achieved. Percent identity is measured over the entire length of a given polynucleotide sequence, eg, as defined by a particular SEQ ID NO, or is obtained over a shorter length, eg, from a longer given polynucleotide sequence May be measured over the length of fragments to be made, eg, fragments of at least 45, at least 60, at least 90, at least 120, at least 150, at least 210 or at least 450 contiguous residues. Such lengths are merely exemplary and for lengths where percent identity can be measured using any fragment length supported by the sequences shown in this specification, tables, figures, or sequence listings. It is understood that this may be explained.
本明細書で同定されるポリペプチド配列に関する「パーセント(%)アミノ酸配列同一性」は、必要に応じて、最高のパーセント配列同一性を達成するために配列を整列させ、ギャップを導入した後の、配列同一性の一部としていかなる保存的置換も考慮しない、第2の参照ポリペプチド配列またはその一部のアミノ酸残基と同一であるクエリー配列中のアミノ酸残基のパーセンテージとして定義される。パーセントアミノ酸配列同一性を決定する目的のためのアラインメントは、例えば、BLAST、BLAST−2、ALIGNまたはMegalign(DNASTAR)ソフトウェアなどの公的に入手可能なコンピュータソフトウェアを使用して、当業者の範囲内の様々な方法で達成することができる。当業者は、比較される配列の全長にわたって最高のアラインメントを達成するために必要な任意のアルゴリズムを含む、アラインメントを測定するための適切なパラメータを決定することができる。パーセント同一性は、例えば、特定の配列番号によって定義されるような所与のポリペプチド配列の全長にわたって測定されるか、またはより短い長さにわたって、例えば、所与のより長いポリペプチド配列から取得される断片、例えば、少なくとも15、少なくとも20、少なくとも30、少なくとも40、少なくとも50、少なくとも70または少なくとも150個の連続残基の断片の長さにわたって測定されてもよい。このような長さは単なる例示であり、本明細書、表、図、または配列表に示される配列によって支持される任意の断片長を用いて、パーセント同一性を測定することができる長さについて説明してもよいことが理解される。 “Percent (%) amino acid sequence identity” with respect to a polypeptide sequence identified herein is, if necessary, after aligning the sequences to achieve the highest percent sequence identity and introducing gaps. , Defined as the percentage of amino acid residues in a query sequence that are identical to a second reference polypeptide sequence or a portion thereof, without considering any conservative substitutions as part of sequence identity. Alignments for the purpose of determining percent amino acid sequence identity are within the purview of those skilled in the art using publicly available computer software such as, for example, BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Can be achieved in various ways. One skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve the best alignment over the full length of the sequences being compared. Percent identity is measured over the entire length of a given polypeptide sequence, eg, as defined by a particular SEQ ID NO, or is obtained over a shorter length, eg, from a given longer polypeptide sequence May be measured over the length of the fragments to be made, eg, fragments of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 consecutive residues. Such lengths are merely exemplary and for lengths where percent identity can be measured using any fragment length supported by the sequences shown in this specification, tables, figures, or sequence listings. It is understood that this may be explained.
「ベクター」は、核酸分子であり、好ましくは、宿主細胞内におよび/または宿主細胞間に挿入された核酸分子を伝達する適切な宿主内で自己複製する。この用語は、主に細胞へのDNAまたはRNAの挿入のために機能するベクター、主にDNAまたはRNAの複製のために機能するベクターの複製、ならびにDNAもしくはRNAの転写および/または翻訳のために機能する発現ベクターを含む。上記の機能の2つ以上を提供するベクターも含まれる。「発現ベクター」は、適切な宿主細胞に導入される場合、ポリペプチド(複数可)に転写および翻訳され得るポリヌクレオチドである。「発現系」は、通常、所望の発現産物を生じるように機能することができる発現ベクターで構成される適切な宿主細胞を暗示する。 A “vector” is a nucleic acid molecule, preferably self-replicating in a suitable host that conveys the nucleic acid molecule inserted into and / or between host cells. The term is used for vectors that function primarily for insertion of DNA or RNA into cells, for replication of vectors that function primarily for replication of DNA or RNA, and for transcription and / or translation of DNA or RNA. Contains a functioning expression vector. Also included are vectors that provide more than one of the above functions. An “expression vector” is a polynucleotide that can be transcribed and translated into polypeptide (s) when introduced into a suitable host cell. An “expression system” usually implies a suitable host cell comprised of an expression vector that can function to yield a desired expression product.
ポリペプチドに適用される「分解抵抗」は、典型的には血清または血漿中、またはタンパク質の貯蔵または送達ビヒクルとして意図される製剤内のプロテアーゼを伴う、血液またはその成分の劣化に耐えるポリペプチドの能力を指す。分解耐性は、典型的には日の範囲(例えば、0.25、0.5、1、2、4、8、16日)の間、−80℃、−20℃、0℃、4℃、25℃、および37℃などの特定の温度で、ヒト(もしくは必要に応じて、マウス、ラット、サル)の血液、血清、血漿、または製剤とタンパク質を組み合わせることによって測定することができる。次いで、試料中のインタクトなタンパク質を、標準的なタンパク質定量法を用いて測定する。タンパク質の50%が分解される時点は、タンパク質の「分解半減期」である。 “Degradation resistance” as applied to a polypeptide typically refers to that of a polypeptide that resists degradation of blood or its components, with proteases in serum or plasma, or in a formulation intended as a protein storage or delivery vehicle. Refers to ability. Degradation resistance is typically −80 ° C., −20 ° C., 0 ° C., 4 ° C. during a range of days (eg, 0.25, 0.5, 1, 2, 4, 8, 16 days), It can be measured by combining human (or mouse, rat, monkey) blood, serum, plasma, or formulation and protein at specific temperatures, such as 25 ° C. and 37 ° C. The intact protein in the sample is then measured using standard protein quantification methods. The point at which 50% of the protein is degraded is the “degradation half-life” of the protein.
「半減期」という用語は、典型的には、薬物の血漿濃度を半分に減少させるのに必要な時間を指す。「半減期」、「t1/2」、「消失半減期」および「循環半減期」という用語は、本明細書において互換的に使用される。 The term “half-life” typically refers to the time required to reduce the plasma concentration of a drug in half. The terms “half-life”, “t 1/2 ”, “elimination half-life” and “circulating half-life” are used interchangeably herein.
「流体力学半径」は、拡散の特性から計算される溶液中での分子の見かけの半径(nm単位のRh)である。タンパク質の「流体力学半径」は、水溶液中での拡散速度ならびに高分子ゲル中を移動する能力に影響を与える。タンパク質の流体力学半径は、その分子量だけでなく、形状および緊密さを含むその構造、ならびにその水和状態によって影響を受ける。DLSおよびサイズ排除クロマトグラフィーなどを用いる流体力学半径を決定するための方法は、当該技術分野において公知である。ほとんどのタンパク質は、タンパク質が最小の流体力学半径を有することができる最もコンパクトな三次元構造である球状構造を有する。いくつかのタンパク質は、ランダムおよびオープン、不定形、または「直鎖状」の構造を採用した結果、同様の分子量の典型的な球状タンパク質と比べてはるかに大きな流体力学半径を有する。 “Hydrodynamic radius” is the apparent radius of a molecule in solution (R h in nm) calculated from the properties of diffusion. The “hydrodynamic radius” of a protein affects the diffusion rate in aqueous solution as well as the ability to move through the polymer gel. The hydrodynamic radius of a protein is influenced not only by its molecular weight, but also by its structure, including shape and tightness, and its hydration state. Methods for determining hydrodynamic radii using DLS and size exclusion chromatography are well known in the art. Most proteins have a globular structure, the most compact three-dimensional structure that allows a protein to have the smallest hydrodynamic radius. Some proteins have a much larger hydrodynamic radius compared to typical globular proteins of similar molecular weight as a result of employing random and open, amorphous, or “linear” structures.
「生理的条件」は、生きている宿主における条件のセットならびに生体のそれらの条件を模倣する温度、塩濃度、pHを含むインビトロ条件下を指す。インビトロアッセイにおける使用のための生理学的に関連する条件の宿主が確立されている。一般的に、生理的緩衝液は、塩の生理的濃度を含有し、約6.5〜約7.8、好ましくは約7.0〜約7.5の範囲の中性pHに調整される。様々な生理的緩衝液がSambrookら(1989)に記載されている。生理学的に関連する温度は、約25℃〜約38℃、好ましくは約35℃〜約37℃の範囲である。 “Physiological conditions” refers to in vitro conditions that include a set of conditions in a living host as well as temperature, salt concentration, pH that mimic those conditions in a living organism. A host of physiologically relevant conditions for use in in vitro assays has been established. In general, the physiological buffer contains a physiological concentration of salt and is adjusted to a neutral pH in the range of about 6.5 to about 7.8, preferably about 7.0 to about 7.5. . Various physiological buffers are described in Sambrook et al. (1989). Physiologically relevant temperatures range from about 25 ° C to about 38 ° C, preferably from about 35 ° C to about 37 ° C.
「制御放出剤」、「徐放剤」、「デポー製剤」または「徐放剤」は、ポリペプチドが薬剤の非存在下で投与される時の放出の持続時間と比べて、本発明のポリペプチドの放出の持続時間を延長することができる薬剤を指すために互換的に使用される。本発明の別の実施形態は、異なる放出速度を有し、異なる治療量をもたらしてもよい。 “Controlled release agent”, “sustained release agent”, “depot formulation” or “sustained release agent” is defined as a polypeptide of the invention as compared to the duration of release when the polypeptide is administered in the absence of the drug. Used interchangeably to refer to an agent that can prolong the duration of peptide release. Another embodiment of the invention may have different release rates, resulting in different therapeutic amounts.
本明細書で使用される「アンタゴニスト」という用語は、本明細書に開示される天然ポリペプチドの生物活性を部分的にまたは完全に阻止、阻害、または中和する任意の分子を含む。ポリペプチドのアンタゴニストを同定するための方法は、候補アンタゴニスト分子と天然ポリペプチドとを接触させること、および通常は天然ポリペプチドと関連する1以上の生物活性の検出可能な変化を測定することを含み得る。本発明の文脈において、アンタゴニストは、タンパク質、核酸、炭水化物、抗体または活性タンパク質の効果を減少させる任意の他の分子を含むことができる。 The term “antagonist” as used herein includes any molecule that partially or fully prevents, inhibits, or neutralizes the biological activity of a native polypeptide disclosed herein. A method for identifying an antagonist of a polypeptide comprises contacting a candidate antagonist molecule with a natural polypeptide, and measuring a detectable change in one or more biological activities normally associated with the natural polypeptide. obtain. In the context of the present invention, antagonists can include proteins, nucleic acids, carbohydrates, antibodies or any other molecule that reduces the effect of the active protein.
「アゴニスト」という用語は、最も広い意味で使用され、本明細書に開示される天然ポリペプチドの生物活性を模倣する任意の分子を含む。適切なアゴニスト分子には、特に、アゴニスト抗体もしくは抗体断片、天然のポリペプチド、ペプチド、小有機分子などの断片またはアミノ酸配列変異体を含む。天然ポリペプチドのアゴニストを同定するための方法は、候補アゴニスト分子と天然ポリペプチドとを接触させること、および通常は天然のポリペプチドに関連する1以上の生物活性における検出可能な変化を測定することを含み得る。 The term “agonist” is used in the broadest sense and includes any molecule that mimics the biological activity of a natural polypeptide disclosed herein. Suitable agonist molecules include, in particular, agonist antibodies or antibody fragments, naturally occurring polypeptides, peptides, fragments of small organic molecules or amino acid sequence variants. A method for identifying an agonist of a natural polypeptide is to contact a candidate agonist molecule with the natural polypeptide and to measure a detectable change in one or more biological activities normally associated with the natural polypeptide. Can be included.
本明細書における目的のための「活性」は、対応する天然活性タンパク質のそれと一致する融合タンパク質の成分の作用または効果を指し、「生物学的活性」または「生物活性」は、受容体結合、アンタゴニスト活性、アゴニスト活性、または細胞応答もしくは生理学的応答を含むがこれらに限定されないインビトロもしくはインビボでの生物学的機能または作用を指す。 “Activity” for purposes herein refers to the action or effect of a component of the fusion protein that matches that of the corresponding naturally active protein, “biological activity” or “biological activity” means receptor binding, Refers to an in vitro or in vivo biological function or action including, but not limited to, antagonist activity, agonist activity, or cellular or physiological response.
本明細書で使用する「治療(treatment)」もしくは「治療(treating)」、または「緩和」もしくは「寛解」は、本明細書において互換的に使用される。これらの用語は、治療上の利点および/または予防上の利点を含むがこれらに限定されない有益なまたは所望の結果を得るためのアプローチを指す。治療上の利点とは、治療される基礎疾患の根絶または改善を意味する。また、対象において改善が観察されるが、対象はまだその基礎疾患を患っている可能性があるように、基礎疾患に関連する生理学的症状のうちの1以上の根絶または改善により、治療上の利点が達成される。予防上の利点のために、特定の疾患を発症するリスクのある対象、またはその疾患の診断がなされていなくても、疾患の生理学的症状のうちの1以上を報告する対象に、本組成物を投与することができる。 As used herein, “treatment” or “treating” or “relief” or “remission” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results, including but not limited to therapeutic and / or prophylactic benefits. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, an improvement is observed in the subject, but the eradication or improvement of one or more of the physiological symptoms associated with the underlying disease may be therapeutic, as the subject may still suffer from the underlying disease. Benefits are achieved. For preventive benefits, the composition may be used in subjects who are at risk of developing a particular disease or who report one or more of the physiological symptoms of the disease even if the disease has not been diagnosed. Can be administered.
本明細書で使用する「治療効果」は、活性タンパク質が保持する抗原性エピトープに対する抗体の産生を誘導する能力以外の、本発明の融合タンパク質によって引き起こされるヒトもしくは他の動物における疾患の治療、緩和、緩解、もしくは予防を含むがこれらに限定されない生理学的効果、またはそうでなければ、ヒトもしくは動物の身体的もしくは精神的幸福を増強する生理学的効果を指す。治療有効量の決定は、特に本明細書に提供される詳細な開示に照らして、十分に当業者の能力の範囲内である。 As used herein, “therapeutic effect” refers to the treatment, alleviation of a disease in a human or other animal caused by a fusion protein of the present invention, other than the ability to induce the production of antibodies to an antigenic epitope carried by the active protein. Refers to a physiological effect including, but not limited to, remission or prevention, or otherwise a physiological effect that enhances the physical or mental well-being of a human or animal. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
本明細書で使用する「治療有効量」および「治療有効用量」という用語は、対象に単回用量または反復用量で投与した場合に、疾患状態もしくは病状の任意の症状、態様、測定されるパラメータまたは特性に対する任意の検出可能で、有益な効果を有することが可能である、単独でのまたは融合タンパク質組成物の一部としての活性タンパク質の量を指す。このような効果は、有益であることが絶対的である必要はない。 As used herein, the terms “therapeutically effective amount” and “therapeutically effective dose” refer to any symptom, aspect, or measured parameter of a disease state or condition when administered to a subject in a single or repeated dose. Or refers to the amount of active protein, alone or as part of a fusion protein composition, that can have any detectable and beneficial effect on the property. Such an effect need not be absolute to be beneficial.
本明細書で使用する「治療的に有効な投与計画」という用語は、単独でのまたは融合タンパク質組成物の一部としての活性タンパク質の連続投与される用量のためのスケジュールを指し、この用量は、疾患状態もしくは病状の任意の症状、態様、測定されるパラメータまたは特性に対して持続した有益な効果をもたらすために治療有効量で与えられる。 As used herein, the term “therapeutically effective dosage regimen” refers to a schedule for consecutively administered doses of active protein, alone or as part of a fusion protein composition, Given in a therapeutically effective amount to produce a sustained beneficial effect on any symptom, aspect, measured parameter or characteristic of the disease state or condition.
融合タンパク質
様々な態様において、本発明は、活性タンパク質に連結されたムチンドメインポリペプチドを含む融合タンパク質を提供する。このようなタンパク質は、「ムチン化(mucinylated)」されたタンパク質とも呼ばれる。本明細書で使用する本発明の「融合タンパク質」は、活性タンパク質に連結されたムチンドメインポリペプチドを含む。一実施形態において、ムチンドメインポリペプチドおよび活性タンパク質は、通常、個々のタンパク質中に存在し、融合タンパク質と結合されるか、またはそれらは、通常同じタンパク質中に存在し得るが、融合タンパク質では新しい配置に置かれる。本発明の組成物および方法は、ムチンドメインポリペプチドと融合した場合に、活性タンパク質の半減期などの薬物動態学的特性を増強するのに特に有用である。一実施形態において、本発明の融合タンパク質は、ムチンドメインポリペプチドに結合していない対応する活性タンパク質の生物活性および/または治療活性の全てまたは一部を保持する。一実施形態において、本発明の融合タンパク質を形成するためにムチンドメインポリペプチドと融合すると、活性タンパク質の治療活性/生物活性が向上する。
In various embodiments, the present invention provides a fusion protein comprising a mucin domain polypeptide linked to an active protein. Such proteins are also referred to as “mucinylated” proteins. As used herein, a “fusion protein” of the present invention comprises a mucin domain polypeptide linked to an active protein. In one embodiment, the mucin domain polypeptide and the active protein are usually present in individual proteins and bound to the fusion protein, or they can usually be present in the same protein, but new in the fusion protein. Put in place. The compositions and methods of the present invention are particularly useful for enhancing pharmacokinetic properties, such as the half-life of an active protein, when fused to a mucin domain polypeptide. In one embodiment, the fusion protein of the invention retains all or part of the biological and / or therapeutic activity of the corresponding active protein that is not bound to the mucin domain polypeptide. In one embodiment, fusion with a mucin domain polypeptide to form a fusion protein of the invention improves the therapeutic / biological activity of the active protein.
一実施形態において、本発明による融合タンパク質は、免疫グロブリン分子またはFcドメインを含む任意の分子、またはそれらの任意の断片を特異的に排除する。一実施形態において、融合タンパク質またはその任意の部分は、α1,3−ガラクトシルトランスフェラーゼまたはβ1,6−アセチルグルコサミニルトランスフェラーゼによってグリコシル化されない。一実施形態において、融合タンパク質は、αGalに特異的な抗体に結合しない。一実施形態において、本発明の融合タンパク質は、Gal α1,3Gal特異的な抗体に結合しない。 In one embodiment, the fusion protein according to the invention specifically excludes any molecule comprising an immunoglobulin molecule or Fc domain, or any fragment thereof. In one embodiment, the fusion protein or any portion thereof is not glycosylated by α1,3-galactosyltransferase or β1,6-acetylglucosaminyltransferase. In one embodiment, the fusion protein does not bind to an antibody specific for αGal. In one embodiment, the fusion proteins of the invention do not bind to Gal α1,3Gal specific antibodies.
ムチンタンパク質およびタンパク質のムチンドメインは、ムチンタンパク質およびムチンドメインを含む他のポリペプチドが硬直したランダムコイルとして動作することを構造的に可能にする高度なグリコシル化を含む。高度にグリコシル化されたムチンドメインを構成する親水性の分枝状親水性炭水化物と組み合わせた、この硬直したランダムコイル構造は、発現タンパク質の分子量に基づいて予想されるものを超える活性タンパク質の流体力学半径を増加させるのに特に有用である。また、高レベルのグリコシル化にとって、ムチンドメインの付加は、活性タンパク質の濃縮溶液の電荷、溶解性および粘弾性特性などのタンパク質の物理化学的特性を変更する可能性も有する。本発明のムチン化された融合タンパク質は、タンパク質の半減期を延長するための従来の戦略を上回るいくつかの利点を有する。本発明の融合タンパク質は、さらなるコンジュゲーションおよび精製ステップを必要としない標準的な発現手段を介して生成することができる。ムチンドメインポリペプチドは、活性タンパク質のN−末端またはC−末端のいずれかを介して活性タンパク質に連結することができる。ムチンドメインポリペプチドは、容積が減少し、生物活性に対して大した影響を与えない単量体の非球状タンパク質であるという点で他の融合パートナーよりも構造的に制限がない。ムチンドメインの使用は、Fcエフェクター機能などの内因性生物活性のリスクを低下させる。ヒト治療薬を調製するために使用する場合、本発明の融合タンパク質は、免疫原性のリスクを減らすために高いグリコシル化を有する完全なヒト配列を含むことができる。 Mucin proteins and mucin domains of proteins contain advanced glycosylation that structurally allows mucin proteins and other polypeptides containing mucin domains to act as rigid random coils. Combined with the hydrophilic branched hydrophilic carbohydrates that make up the highly glycosylated mucin domain, this rigid random coil structure is more than expected based on the molecular weight of the expressed protein. It is particularly useful for increasing the radius. For high levels of glycosylation, the addition of mucin domains also has the potential to alter protein physicochemical properties such as charge, solubility and viscoelastic properties of active protein concentrated solutions. The mucinized fusion proteins of the present invention have several advantages over conventional strategies for extending the half-life of the protein. The fusion proteins of the invention can be generated via standard expression means that do not require additional conjugation and purification steps. The mucin domain polypeptide can be linked to the active protein via either the N-terminus or C-terminus of the active protein. Mucin domain polypeptides are less structurally limited than other fusion partners in that they are monomeric, non-globular proteins that are reduced in volume and do not significantly affect biological activity. The use of mucin domains reduces the risk of endogenous biological activities such as Fc effector function. When used to prepare human therapeutics, the fusion proteins of the invention can include fully human sequences with high glycosylation to reduce the risk of immunogenicity.
結果として生じる機能的特性または生物活性および薬理学的活性ならびにパラメータを含む本発明の融合タンパク質組成物の活性は、所望の特性を測定するための、当技術分野で公知の任意の適切なスクリーニングアッセイによって決定することができる。融合タンパク質の活性および構造は、本発明の組成物の半減期、溶解度、構造および生物活性の保持ならびに本発明の融合タンパク質ではない活性タンパク質との比較を確定するために、本明細書に記載のアッセイ、実施例のアッセイによって、または当技術分野で公知の方法によって測定することができる。 The resulting functional properties or activity of the fusion protein composition of the present invention, including biological and pharmacological activities and parameters, is determined by any suitable screening assay known in the art for measuring the desired properties. Can be determined by. The activity and structure of the fusion protein are described herein to determine the retention of half-life, solubility, structure and biological activity of the compositions of the invention and comparison with active proteins that are not fusion proteins of the invention. It can be measured by assays, example assays or by methods known in the art.
融合タンパク質に言及する場合、「連結された」または「融合された」もしくは「融合」という用語は、ムチンドメインポリペプチドおよび活性タンパク質が、ムチンドメインポリペプチドのO−結合グリコシル化を可能にし、活性タンパク質の活性を維持する方法で、細胞内で単一ポリペプチドとして発現することを示すものと意図される。一実施形態において、ムチンドメインポリペプチドは、必要に応じて、アミノ酸リンカーを介して活性タンパク質に連結することができる。アミノ酸リンカーは、さらに必要に応じて、対象への融合タンパク質の投与に際して活性タンパク質を放出するように設計され得る切断配列を含んでもよい。 When referring to a fusion protein, the term “linked” or “fused” or “fusion” means that the mucin domain polypeptide and the active protein are capable of O-linked glycosylation of the mucin domain polypeptide and active. It is intended to indicate that the protein is expressed as a single polypeptide in the cell in a manner that maintains the activity of the protein. In one embodiment, the mucin domain polypeptide can optionally be linked to the active protein via an amino acid linker. The amino acid linker may further comprise a cleavage sequence that can be designed to release the active protein upon administration of the fusion protein to the subject, if desired.
必要に応じて、ムチンドメインポリペプチドに融合された活性タンパク質を含む融合タンパク質は、さらに、活性を増強するか、または融合タンパク質にさらなる活性を付与することが意図される1以上の追加の部分に融合されてもよい。一実施形態において、この融合タンパク質は、構造:A−M−Bを含み、式中、AはN末端融合パートナーであり、Mはムチンドメインであり、Bは、C末端融合パートナーである。AおよびBは、類似しているおよび異なるアイデンティティを含んでもよい。この実施形態の一態様において、AおよびBは、アゴニズム、アンタゴニズム、酵素活性、特異的なタンパク質もしくは細胞への標的化、化学反応性、またはオリゴマー化を含むがこれらに限定されない方法で、独立してまたは相乗的に作用することができる生物活性のある部分である。別の態様において、AおよびBが同じである場合、活性の増強は、結合活性を介して促進される。 Optionally, a fusion protein comprising an active protein fused to a mucin domain polypeptide can be further added to one or more additional moieties that are intended to enhance activity or confer additional activity to the fusion protein. It may be fused. In one embodiment, the fusion protein comprises the structure: AMB, wherein A is an N-terminal fusion partner, M is a mucin domain, and B is a C-terminal fusion partner. A and B may include similar and different identities. In one aspect of this embodiment, A and B are independent in a manner that includes, but is not limited to, agonism, antagonism, enzymatic activity, specific protein or cellular targeting, chemical reactivity, or oligomerization. A biologically active moiety that can act in synergy or synergistic manner. In another embodiment, when A and B are the same, the enhancement of activity is facilitated through binding activity.
本発明の融合タンパク質は、標準的な組換えDNA技術によって産生することができる。例えば、異なるポリペプチド配列をコードするDNA断片は、従来の技術に従って、例えば、ライゲーションのための平滑末端またはシグザグ末端(stagger−ended termini)、適切な末端を提供するための制限酵素消化、必要に応じて付着末端の補充、望ましくない結合を回避するためのアルカリホスファターゼ処理、および酵素によるライゲーションによってインフレームで共に連結される。別の実施形態において、融合遺伝子は、自動DNA合成機を含む従来の技術によって合成することができる。あるいは、遺伝子断片のPCR増幅を、2つの連続した遺伝子断片の間に相補的オーバーハングをもたらすアンカープライマーを用いて行い、その後、アニールおよび再増幅を行って、キメラ遺伝子配列を生成することができる(例えば、Ausubel et al.(編)Current Protocols in Molecular Biology,John Wiley&Sons,1992参照)。融合部分を補助するための多くの発現ベクターは、市販されており、以下でより詳細に説明される。 The fusion proteins of the invention can be produced by standard recombinant DNA techniques. For example, DNA fragments encoding different polypeptide sequences can be ligated according to conventional techniques, for example, blunt or stag-terminated termini for ligation, restriction enzyme digestion to provide appropriate ends, necessary Accordingly, they are ligated together in frame by supplementing sticky ends, alkaline phosphatase treatment to avoid undesired binding, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be performed using anchor primers that provide a complementary overhang between two consecutive gene fragments, followed by annealing and reamplification to generate a chimeric gene sequence. (See, eg, Ausubel et al. (Eds.) Current Protocols in Molecular Biology, John Wiley & Sons, 1992). Many expression vectors for assisting the fusion moiety are commercially available and are described in more detail below.
ムチンドメインポリペプチド
「ムチンドメインポリペプチド」は、「ムチンドメイン」を含む任意のタンパク質として本明細書で定義される。ムチンドメインは、潜在的なグリコシル化部位が豊富であり、ムチンドメイン内のアミノ酸の40%以上を示し得るセリンおよび/またはスレオニンならびにプロリンの含有量が高い。ムチンドメインは、主にO−結合型グリカンで高度にグリコシル化されている。ムチンドメインポリペプチドは、グリカンによってその質量の少なくとも約60%、少なくとも70%、少なくとも80%、または少なくとも90%を有する。ムチンドメインの長さは、各タンデムリピート単位当たり約8個のアミノ酸〜150個のアミノ酸で変化し得るタンデムアミノ酸リピート単位(本明細書ではTRとも呼ぶ)を含むことができる。タンデムリピート単位の数は、本発明のムチンドメインポリペプチドにおいて1〜25個の間で変化し得る。
A mucin domain polypeptide “mucin domain polypeptide” is defined herein as any protein comprising a “mucin domain”. The mucin domain is rich in potential glycosylation sites and has a high content of serine and / or threonine and proline that may represent 40% or more of the amino acids in the mucin domain. The mucin domain is highly glycosylated mainly with O-linked glycans. A mucin domain polypeptide has at least about 60%, at least 70%, at least 80%, or at least 90% of its mass by a glycan. The length of the mucin domain can include a tandem amino acid repeat unit (also referred to herein as TR) that can vary from about 8 amino acids to 150 amino acids for each tandem repeat unit. The number of tandem repeat units can vary between 1 and 25 in the mucin domain polypeptides of the invention.
本発明のムチンドメインポリペプチドは、ムチンタンパク質を含むが、これらに限定されない。「その一部」は、ムチンポリペプチドリンカーが、ムチンタンパク質の少なくとも1つのムチンドメインを含むことを意味する。ムチンタンパク質は、MUC遺伝子(すなわち、MUC1、MUC2、MUC3A、MUC3B、MUC4、MUC5AC、MUC5B、MUC6、MUC7、MUC8、MUC9、MUC11、MUC12、MUC13、MUC15、MUC16、MUC17、MUC19、MUC20、MUC21)によってコードされる任意のタンパク質を含む。ムチンタンパク質のムチンドメインは、典型的には、非反復アミノ酸領域のいずれかの側に隣接している。ムチンドメインポリペプチドは、ムチンタンパク質の細胞外部分、ムチンタンパク質のシグナル配列部分、ムチンタンパク質の膜貫通ドメイン、および/またはムチンタンパク質の細胞質ドメインを含むムチンタンパク質(例えば、MUC20)の全てまたは一部を含んでもよい。ムチンドメインポリペプチドは、可溶性ムチンタンパク質の全てまたは一部を含むことができる。好ましくは、ムチンドメインポリペプチドは、ムチンタンパク質の細胞外部分を含む。 Mucin domain polypeptides of the present invention include, but are not limited to, mucin proteins. “Part thereof” means that the mucin polypeptide linker comprises at least one mucin domain of a mucin protein. Mucin proteins are MUC genes (ie, MUC1, MUC2, MUC3A, MUC3B, MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC8, MUC9, MUC11, MUC12, MUC13, MUC15, MUC15, MUC15, MUC15, MUC15, MUC15, Includes any encoded protein. The mucin domain of a mucin protein is typically adjacent to either side of a non-repeating amino acid region. A mucin domain polypeptide comprises all or part of a mucin protein (eg, MUC20) comprising the extracellular portion of the mucin protein, the signal sequence portion of the mucin protein, the transmembrane domain of the mucin protein, and / or the cytoplasmic domain of the mucin protein. May be included. The mucin domain polypeptide can include all or part of a soluble mucin protein. Preferably, the mucin domain polypeptide comprises the extracellular portion of a mucin protein.
ムチンドメインポリペプチドはまた、ムチンドメインを含むタンパク質の全てまたは一部も含むことができるが、それはMUC遺伝子によってコードされていない。MUC遺伝子はコードしないが、ムチンドメインを含むこのような天然タンパク質には、膜貫通免疫グロブリンおよびムチンドメイン(TIM)ファミリータンパク質、フラクタルカイン(ニューロタクチン)、P−セレクチン糖タンパク質リガンド1(PSGL−1、CD162)、E−セレクチン、L−セレクチン、P−セレクチン、CD34、CD43(ロイコシアリン、シアロホリン(sialophorin))、CD45、CD68、CD96、CD164、GlyCAM−1、MAdCAM、赤血球グリコホリン、グリコカリシン、グリコホリン、LDL−R、ZP3、エンドシアリン、崩壊促進因子(daf、CD55)、ポドカリキシン、エンドグリカン、α−ジストログリカン、ニューロファスチン、EMR1、EMR2、EMR3、EMR4、ETLおよびエピグリカニンなどの膜アンカータンパク質が含まれるが、これらに限定されない。 A mucin domain polypeptide can also include all or part of a protein containing a mucin domain, but it is not encoded by the MUC gene. Such natural proteins that do not encode the MUC gene but contain mucin domains include transmembrane immunoglobulin and mucin domain (TIM) family proteins, fractalkine (neurotactin), P-selectin glycoprotein ligand 1 (PSGL- 1, CD162), E-selectin, L-selectin, P-selectin, CD34, CD43 (leucosialin, sialophorin), CD45, CD68, CD96, CD164, GlyCAM-1, MAdCAM, erythrocyte glycophorin, glycocalicin, glycophorin, LDL-R, ZP3, endosialin, decay accelerating factor (daf, CD55), podocalyxin, endoglycan, α-dystroglycan, neurofastin, EMR1, EMR , EMR3, EMR4, ETL and Epigurikanin including but membrane anchor protein, such as, but not limited to.
ムチンドメインポリペプチドはまた、その用語が本明細書で定義されるようなムチンドメインを有する非天然ポリペプチドを含んでもよい。一実施形態において、ムチンドメインポリペプチドは、本発明に従ってムチンドメインを含むように新規に設計される。 A mucin domain polypeptide may also include a non-natural polypeptide having a mucin domain, as that term is defined herein. In one embodiment, mucin domain polypeptides are newly designed to include mucin domains according to the present invention.
一実施形態において、ムチンドメインポリペプチドは、Pro、SerおよびThrに富むアミノ酸のタンデムリピートドメインを含む。この実施形態の一態様において、本発明のムチンドメインポリペプチド内のタンデムリピート単位数は、1〜25個である。好ましくは、ムチンドメインポリペプチド内のタンデムリピート単位数は、2〜20個である。より好ましくは、ムチンドメインポリペプチド内のタンデムリピート単位数は、少なくとも約4個である。この実施形態のさらなる態様において、本発明のムチンドメインポリペプチド内のセリンおよび/またはスレオニンならびにプロリン残基の割合は、少なくとも10%である。好ましくは、本発明のムチンドメインポリペプチド内のセリンおよび/またはスレオニンならびにプロリン残基の割合は、少なくとも20%である。より好ましくは、本発明のムチンドメインポリペプチド内のセリンおよび/またはスレオニンならびにプロリン残基の割合は、30%を超える。この実施形態の最後の態様において、ムチンドメイン内の各タンデムアミノ酸リピート単位は、少なくとも8個のアミノ酸で構成されている。好ましくは、各単位は、少なくとも16個のアミノ酸で構成されている。より好ましくは、各単位は、少なくとも19個のアミノ酸で構成され、各単位の長さは、約19個のアミノ酸〜150個のアミノ酸で変化してもよい。 In one embodiment, the mucin domain polypeptide comprises a tandem repeat domain of amino acids rich in Pro, Ser and Thr. In one aspect of this embodiment, the number of tandem repeat units in the mucin domain polypeptide of the invention is 1-25. Preferably, the number of tandem repeat units in the mucin domain polypeptide is 2-20. More preferably, the number of tandem repeat units within the mucin domain polypeptide is at least about 4. In a further aspect of this embodiment, the proportion of serine and / or threonine and proline residues in the mucin domain polypeptide of the invention is at least 10%. Preferably, the proportion of serine and / or threonine and proline residues in the mucin domain polypeptide of the invention is at least 20%. More preferably, the proportion of serine and / or threonine and proline residues within the mucin domain polypeptide of the invention is greater than 30%. In the last aspect of this embodiment, each tandem amino acid repeat unit within the mucin domain is composed of at least 8 amino acids. Preferably, each unit is composed of at least 16 amino acids. More preferably, each unit is composed of at least 19 amino acids, and the length of each unit may vary from about 19 amino acids to 150 amino acids.
一実施形態において、ムチンドメインポリペプチドは、少なくとも40%のセリン、スレオニン、およびプロリンを含む少なくとも32個のアミノ酸を含む。一実施形態において、本発明によるムチンドメインポリペプチドは、タンデムリピート単位当たり少なくとも8個のアミノ酸長のタンデムリピートアミノ酸単位を少なくとも2、4、8、10または12個を含む。タンデムリピート単位の好ましいアミノ酸配列には、表Iのものが含まれるが、これらに限定されない。ムチンドメインポリペプチド、および/またはムチンドメインポリペプチドをコードする核酸は、当該技術分野で公知であり、GenBankなどの供給源から公的に入手可能であるタンパク質のムチンドメインコード配列を用いて構築されてもよい。 In one embodiment, the mucin domain polypeptide comprises at least 32 amino acids including at least 40% serine, threonine, and proline. In one embodiment, the mucin domain polypeptide according to the present invention comprises at least 2, 4, 8, 10 or 12 tandem repeat amino acid units at least 8 amino acids long per tandem repeat unit. Preferred amino acid sequences of tandem repeat units include, but are not limited to those of Table I. Mucin domain polypeptides and / or nucleic acids encoding mucin domain polypeptides are constructed using mucin domain coding sequences of proteins known in the art and publicly available from sources such as GenBank. May be.
PTS→ プロリン/セリン/スレオニンに富む配列。
* → 概算;TR数は、ほとんどの場合の範囲として報告する。
+ → Uniprot番号
∞ →TRの数は特定の領域で異なる。
NA → 公表せず。
PTS → Proline / serine / threonine rich sequence.
* → Estimated; TR number is reported as the range in most cases.
+ → Uniprot number ∞ → The number of TR differs in a specific region.
NA → Not announced.
一実施形態において、ムチンドメインポリペプチドの全長配列は32〜200である。半減期の延長は、流体力学半径、および最も重要なことだが、腎臓ろ過の迂回を可能にする約60kDを超える見かけの分子量の増大と相関するので、ムチンドメインポリペプチドの長さは、活性部分のサイズに多少依存する。例えば、5kD未満の分子量のペプチドは、所望の半減期の延長を達成するために、200個のアミノ酸のムチンドメインポリペプチドを必要とし得る。対照的に、40kDの分子量のタンパク質は、所望の半減期を達成するために、32個のアミノ酸のムチンドメインポリペプチドのみを必要とし得る。さらに、ムチン化は、融合タンパク質のムチンドメインペプチドにおけるムチンタンデムリピート数を増加または減少させることによって半減期の最適化を可能にする。 In one embodiment, the full-length sequence of a mucin domain polypeptide is 32-200. The length of the mucin domain polypeptide depends on the hydrodynamic radius and, most importantly, the apparent molecular weight increase above about 60 kD that allows bypassing renal filtration, so Depends somewhat on the size of the. For example, a peptide with a molecular weight of less than 5 kD may require a 200 amino acid mucin domain polypeptide to achieve the desired half-life extension. In contrast, a 40 kD molecular weight protein may require only a 32 amino acid mucin domain polypeptide to achieve the desired half-life. Furthermore, mucinization allows optimization of half-life by increasing or decreasing the number of mucin tandem repeats in the mucin domain peptide of the fusion protein.
あるいは、ムチンドメインポリペプチド部分は、野生型タンパク質の天然ムチンドメイン配列に変異を有する変異型ムチンドメインポリペプチドとして提供される。例えば、変異型ムチンドメインポリペプチドは、野生型ムチンドメインポリペプチドと比較して、追加のO−結合型グリコシル化部位を含む。あるいは、変異型ムチンドメインポリペプチドは、野生型ムチンドメインポリペプチドと比較して、セリン、スレオニン、またはプロリン残基の数の増加をもたらすアミノ酸配列の変異を含む。あるいは、変異型ムチンドメインポリペプチド配列は、特定のpHにおけるpIまたは分子の電荷を変更するアスパラギン酸、グルタミン酸、リジン、ヒスチジン、およびアルギニンを含むがこれらに限定されない、追加されるかまたは差し引かれた荷電残基を含む。 Alternatively, the mucin domain polypeptide portion is provided as a mutant mucin domain polypeptide having a mutation in the native mucin domain sequence of the wild type protein. For example, a mutant mucin domain polypeptide contains an additional O-linked glycosylation site compared to a wild type mucin domain polypeptide. Alternatively, a mutant mucin domain polypeptide comprises an amino acid sequence variation that results in an increase in the number of serine, threonine, or proline residues as compared to a wild type mucin domain polypeptide. Alternatively, mutant mucin domain polypeptide sequences are added or subtracted including, but not limited to, aspartic acid, glutamic acid, lysine, histidine, and arginine that alter pi or molecular charge at a particular pH. Contains charged residues.
活性タンパク質および治療活性タンパク質
本明細書で使用され、本発明の融合タンパク質に含まれる「活性タンパク質」とは、生物学的、治療的、予防的、もしくは診断的な関心または機能のタンパク質を意味し、かつ/または生物活性を媒介することができる。この用語が本明細書で使用されるとおり、「治療活性タンパク質」は、対象に投与した場合に、疾患、障害もしくは病状を予防または改善することができるタンパク質である。
Active protein and therapeutic active protein As used herein, an “active protein” included in the fusion protein of the present invention means a protein of biological, therapeutic, prophylactic, or diagnostic interest or function. And / or mediate biological activity. As the term is used herein, a “therapeutically active protein” is a protein that can prevent or ameliorate a disease, disorder or condition when administered to a subject.
一実施形態において、本発明による活性タンパク質または治療活性タンパク質は、具体的には、Fcドメインを含む免疫グロブリン分子またはそれらの任意の断片を排除する。 In one embodiment, the active protein or therapeutically active protein according to the present invention specifically excludes an immunoglobulin molecule comprising an Fc domain or any fragment thereof.
特に興味深いのは、薬物動態学的パラメータの増加、溶解性の増加、安定性の増加、もしくはいくつかの他の強化された薬学的特性が求められる活性タンパク質および治療活性タンパク質であるか、あるいは半減期の延長が、有効性、安全性を向上させるかまたは投与頻度の減少および/もしくは患者のコンプライアンスの向上をもたらす活性タンパク質である。したがって、本発明の融合タンパク質は、ムチンドメインポリペプチドに連結されていない活性タンパク質と比較して、治療活性タンパク質の治療効力を向上させること、例えば、対象に投与された場合に、インビボ曝露または本発明の融合タンパク質が治療枠内に留まる時間の長さを増加させることを含むことを考慮して、様々な目的で調製される。 Of particular interest are active and therapeutically active proteins that require increased pharmacokinetic parameters, increased solubility, increased stability, or some other enhanced pharmaceutical properties, or halved Prolongation of the phase is an active protein that improves efficacy, safety or results in reduced dosing frequency and / or improved patient compliance. Accordingly, the fusion proteins of the present invention improve the therapeutic efficacy of a therapeutically active protein compared to an active protein that is not linked to a mucin domain polypeptide, e.g., in vivo exposure or Inventive fusion proteins are prepared for a variety of purposes, taking into account increasing the length of time that they remain within the therapeutic window.
一実施形態において、本発明の融合タンパク質は、(以下でより完全に説明するように)ムチンドメインポリペプチドに連結された単一活性タンパク質を含むことができる。別の実施形態において、本発明の融合タンパク質は、1以上のムチンドメインポリペプチドを介して連結された2種類の活性タンパク質を含む融合タンパク質をもたらす第1の活性タンパク質および同じ活性タンパク質の第2の分子を含むことができる。別の実施形態において、本発明の融合タンパク質は、1以上のムチンドメインポリペプチドを介して連結され、異なる活性を有する2種類の活性タンパク質を含む融合タンパク質をもたらす第1活性タンパク質および第2の異なる活性タンパク質を含むことができる。 In one embodiment, the fusion proteins of the invention can comprise a single active protein linked to a mucin domain polypeptide (as described more fully below). In another embodiment, the fusion protein of the invention comprises a first active protein and a second of the same active protein that results in a fusion protein comprising two active proteins linked via one or more mucin domain polypeptides. Molecules can be included. In another embodiment, the fusion protein of the invention is linked via one or more mucin domain polypeptides, resulting in a fusion protein comprising two active proteins having different activities, a first active protein and a second different protein An active protein can be included.
一実施形態において、活性タンパク質は、インビボで使用されるか、またはインビトロアッセイで利用される場合に、所与の標的または別の所望の生物学的特性に対して結合特異性を示す。例えば、活性タンパク質は、アゴニスト、受容体、リガンド、アンタゴニスト、酵素、またはホルモンであり得る。特に興味深いのは、疾患または障害のために使用されるかまたは疾患または障害に有用であることが知られている活性タンパク質であり、その際、半減期の延長は投与頻度の減少または薬理学的効果の増強を可能にする。最小有効用量または血中濃度(Cmin)と最大耐用量または血中濃度(Cmax)との間の狭い治療枠を有する活性タンパク質も興味深い。このような場合には、ムチンドメインポリペプチドを含む融合タンパク質に活性タンパク質を結合させると、ムチンドメインポリペプチドに連結されていない活性タンパク質と比較して、それらの特性が向上し、治療薬または予防薬としてより有用なものにさせることができる。 In one embodiment, the active protein exhibits binding specificity for a given target or another desired biological property when used in vivo or utilized in an in vitro assay. For example, the active protein can be an agonist, receptor, ligand, antagonist, enzyme, or hormone. Of particular interest are active proteins that are used for or known to be useful for a disease or disorder, in which an increase in half-life is a decrease in dosing frequency or pharmacological Enables enhanced effects. Also of interest are active proteins that have a narrow therapeutic window between the minimum effective dose or blood concentration (C min ) and the maximum tolerated dose or blood concentration (C max ). In such cases, binding an active protein to a fusion protein containing a mucin domain polypeptide improves their properties compared to an active protein that is not linked to a mucin domain polypeptide and can be used as a therapeutic or prophylactic agent. It can be made more useful as a medicine.
治療活性タンパク質である本発明の活性タンパク質は、グルコースおよびインスリン障害、代謝障害、心臓血管疾患、血液凝固/出血性障害、成長の障害もしくは病状、腫瘍化の状態、炎症状態、自己免疫状態、ならびに他の疾患および疾患カテゴリーを含むがこれらに限定されず、ムチンドメインポリペプチドに結合していない治療用タンパク質もしくはペプチドが準最適な半減期を示すか、または治療用タンパク質もしくはペプチドが存在しない様々な治療カテゴリーまたは疾患カテゴリーの治療に有用性を有し得る。 The active proteins of the present invention that are therapeutically active proteins include glucose and insulin disorders, metabolic disorders, cardiovascular diseases, blood coagulation / hemorrhagic disorders, growth disorders or conditions, neoplastic conditions, inflammatory conditions, autoimmune conditions, and Various, including but not limited to other diseases and disease categories, a therapeutic protein or peptide that is not bound to a mucin domain polypeptide exhibits a sub-optimal half-life, or a therapeutic protein or peptide is not present It may have utility in treating a treatment category or disease category.
本発明の活性タンパク質は、天然の全長タンパク質であり得るか、または天然の活性タンパク質の治療活性の少なくとも一部を保持している活性タンパク質の断片もしくは配列変異体であり得る。一実施形態において、本発明による活性タンパク質は、天然に見出されるタンパク質に対応する配列を有する組換えポリペプチドであり得る。別の実施形態において、この活性タンパク質は、天然の活性タンパク質の生物活性の少なくとも一部を保持する天然の配列の配列変異体、断片、ホモログ、および模倣物であり得る。 The active protein of the present invention can be a natural full-length protein or can be a fragment or sequence variant of the active protein that retains at least a portion of the therapeutic activity of the natural active protein. In one embodiment, the active protein according to the present invention may be a recombinant polypeptide having a sequence corresponding to a protein found in nature. In another embodiment, the active protein can be a sequence variant, fragment, homologue, and mimetic of a native sequence that retains at least a portion of the biological activity of the native active protein.
非限定的な実施例において、活性タンパク質は、天然の活性タンパク質もしくは天然の活性タンパク質の変異体と少なくとも約80%の配列同一性、または81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、もしくは100%の配列同一性を示す配列であり得る。このようなタンパク質およびペプチドには、以下のものが含まれるがこれらに限定されない:(GLP−1、エキセンジン−4、オキシトシン、オピエートペプチドなどの)生物活性ペプチド、サイトカイン、成長因子、ケモカイン、リンホカイン、リガンド、受容体、ホルモン、酵素、抗体および抗体断片、ドメイン抗体、ナノボディ、一本鎖抗体、DARPin、センチリン(centyrin)、アドネクチンなどの改変抗体の「代替骨格(alternative scaffold)」、ならびに成長因子。受容体の例としては、TNFR2、VEGF受容体、IL−1R1、IL−1RAcP、IL−4受容体、hGH受容体、CTLA−4、PD−1、IL−6Rα、FGF受容体などの)膜結合受容体の細胞外ドメイン、それらの膜貫通ドメインから切断された可溶性受容体、(IL−1RII、TNFRSF11B、DcR3などの)「ダミー」もしくは「デコイ」受容体、および任意の化学的または遺伝的に修飾された可溶性受容体が挙げられる。酵素の例としては、活性化プロテインC、第VII因子、コラゲナーゼ、アガルシダーゼベータ、ドルナーゼα、アルテプラーゼ、ペグ化アスパラギナーゼ、アスパラギナーゼおよびイミグルセラーゼが挙げられる。特定のポリペプチドまたはタンパク質の例としては、顆粒球マクロファージコロニー刺激因子(GM−CSF)、顆粒球コロニー刺激因子(G−CSF)、マクロファージコロニー刺激因子(M−CSF)、コロニー刺激因子(CSF)、インターフェロンβ(IFN−β)、インターフェロンγ(IFNγ)、インターフェロンガンマ誘導因子I(IGIF)、形質転換成長因子ベータ(TGF−β)、RANTES(regulated upon activation,normal T−cell expressed and presumably secreted)、マクロファージ炎症性タンパク質(例えば、MIP−1−αおよびΜΙΡ−1−β、リーシュマニア伸長開始因子(LEIF)、血小板由来増殖因子(PDGF)、腫瘍壊死因子(TNF)、成長因子、例えば、表皮成長因子(EGF)、血管内皮増殖因子(VEGF)、線維芽細胞増殖因子(FGF)、神経成長因子(NGF)、脳由来神経栄養因子(BDNF)、ニューロトロフィン−2(NT−2)、ニューロトロフィン−3(NT−3)、ニューロトロフィン−4(NT−4)、ニューロトロフィン−5(NT−5)、グリア細胞株由来神経栄養因子(GDNF)、毛様体神経栄養因子(CNTF)、TNFタイプII受容体、エリスロポエチン(EPO)、インスリンおよび可溶性糖タンパク質、例えば、gp120およびgp160糖タンパク質が挙げられる。gp120糖タンパク質は、ヒト免疫不全ウイルス(HIV)エンベロープタンパク質であり、gp160糖タンパク質はgp120糖タンパク質に対する既知の前駆体である。 In a non-limiting example, the active protein has at least about 80% sequence identity, or 81%, 82%, 83%, 84%, 85%, with the natural active protein or a variant of the natural active protein, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity It can be the sequence shown. Such proteins and peptides include, but are not limited to: bioactive peptides (such as GLP-1, exendin-4, oxytocin, opiate peptides), cytokines, growth factors, chemokines, lymphokines, “Alternative scaffolds” of modified antibodies such as ligands, receptors, hormones, enzymes, antibodies and antibody fragments, domain antibodies, nanobodies, single chain antibodies, DARPin, centrin, adnectin, and growth factors. Examples of receptors include TNFR2, VEGF receptor, IL-1R1, IL-1RAcP, IL-4 receptor, hGH receptor, CTLA-4, PD-1, IL-6Rα, FGF receptor) Extracellular domains of bound receptors, soluble receptors cleaved from their transmembrane domains, “dummy” or “decoy” receptors (such as IL-1RII, TNFRSF11B, DcR3), and any chemical or genetic And soluble receptors modified. Examples of enzymes include activated protein C, factor VII, collagenase, agarcidase beta, dornase α, alteplase, pegylated asparaginase, asparaginase and imiglucerase. Examples of specific polypeptides or proteins include granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), colony stimulating factor (CSF) , Interferon β (IFN-β), interferon γ (IFNγ), interferon gamma-inducible factor I (IGIF), transforming growth factor beta (TGF-β), RANTES (regulated up activation, normal T-cell expressed and presectable) Macrophage inflammatory proteins (eg, MIP-1-α and ΜΙΡ-1-β, leishmania elongation initiation factor (LEIF), platelet derived growth factor (PDGF), tumor destruction Factors (TNF), growth factors such as epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), Neurotrophin-2 (NT-2), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), neurotrophin-5 (NT-5), glial cell line-derived neurotrophic Factor (GDNF), ciliary neurotrophic factor (CNTF), TNF type II receptor, erythropoietin (EPO), insulin and soluble glycoproteins such as gp120 and gp160 glycoproteins, which are human immune Deficiency virus (HIV) envelope protein, the gp160 glycoprotein is a gp120 glycoprotein It is a known precursor to Park protein.
一実施形態において、生物活性ポリペプチドはGLP−1である。別の実施形態において、生物活性ポリペプチドは、ネシリチド、ヒトB型ナトリウム利尿ペプチド(hBNP)である。さらに別の実施形態において、生物活性ポリペプチドは、27個のアミノ酸からなる天然のブタセクレチンと同一のアミノ酸配列で構成されたペプチドホルモンであるセクレチンである。一実施形態において、生物活性ポリペプチドは、CD4+細胞とHIV−1の融合物の阻害剤である、36個のアミノ酸の一本鎖合成ポリペプチドのエンフビルチドである。一実施形態において、生物活性ポリペプチドは、特異的で、可逆的な直接トロンビン阻害剤のビバリルジンである。抗血友病因子(AHF)は、活性ポリペプチドとして選択されてもよい。HEMOFIL M(商標)AHFの生体内半減期の平均値は14.7±5.1時間(n=61)であることが知られている。別の実施形態において、エリスロポエチンは、生物活性ポリペプチドである。エリスロポエチンは、組換えDNA技術によって製造される165個のアミノ酸の糖タンパク質であり、内因性エリスロポエチンと同じ生物学的効果を有する。慢性腎不全の成人および小児患者では、静脈内投与後の未修飾血漿エリスロポエチンの排出半減期は、4〜13時間の範囲であることが知られている。さらに別の実施形態において、生物活性ポリペプチドはレテプラーゼある。レテプラーゼは、クリングル2およびヒトtPAのプロテアーゼドメインを含む組織プラスミノーゲンアクチベータ(tPA)の非グリコシル化欠失変異タンパク質である。血栓溶解活性の測定に基づいて、未修飾レテプラーゼの有効半減期は、約15分であることが知られている。
In one embodiment, the bioactive polypeptide is GLP-1. In another embodiment, the bioactive polypeptide is nesiritide, human B-type natriuretic peptide (hBNP). In yet another embodiment, the biologically active polypeptide is secretin, a peptide hormone composed of the same amino acid sequence as native porcine secretin consisting of 27 amino acids. In one embodiment, the bioactive polypeptide is enfuvirtide, a 36 amino acid single chain synthetic polypeptide that is an inhibitor of a fusion of CD4 + cells and HIV-1. In one embodiment, the bioactive polypeptide is the specific and reversible direct thrombin inhibitor bivalirudin. Antihemophilic factor (AHF) may be selected as the active polypeptide. It is known that the average in vivo half-life of HEMOFIL M ™ AHF is 14.7 ± 5.1 hours (n = 61). In another embodiment, erythropoietin is a bioactive polypeptide. Erythropoietin is a 165 amino acid glycoprotein produced by recombinant DNA technology and has the same biological effects as endogenous erythropoietin. In adult and pediatric patients with chronic renal failure, the elimination half-life of unmodified plasma erythropoietin after intravenous administration is known to be in the range of 4-13 hours. In yet another embodiment, the biologically active polypeptide is a reteplase. Reteplase is a non-glycosylated deletion mutant protein of tissue plasminogen activator (tPA) that contains the protease domain of
好ましい一実施形態において、活性ポリペプチドは、組換え型のヒトインターロイキン−1受容体アンタゴニスト(IL−IRa)の非グリコシル化形態のアナキンラまたは哺乳類細胞で発現させたグリコシル化形態である。一例において、アナキンラは、153個のアミノ酸からなり、17.3キロダルトンの分子量を有する。アナキンラは、大腸菌細菌発現系を用いて組換えDNA技術によって生成することができる。IL−IRaのグリコシル化バージョンは、哺乳類発現系で生成することができる。未修飾アナキンラのインビボ半減期は、4〜6時間の範囲であることが知られている。 In a preferred embodiment, the active polypeptide is a non-glycosylated form of anakinra or a glycosylated form expressed in mammalian cells of a recombinant human interleukin-1 receptor antagonist (IL-IRa). In one example, anakinra consists of 153 amino acids and has a molecular weight of 17.3 kilodaltons. Anakinra can be produced by recombinant DNA technology using an E. coli bacterial expression system. A glycosylated version of IL-IRa can be produced in a mammalian expression system. The in vivo half-life of unmodified anakinra is known to be in the range of 4-6 hours.
別の好ましい実施形態において、活性ポリペプチドは、エキセンジン−4である。一例において、エキセンジン−4は39個のアミノ酸からなる。エキセンジン−4は、大腸菌細菌発現系を用いた組換えDNA技術によって生成することができる。未修飾エキセンジン−4のインビボ半減期は、0.5時間ivであることが知られている(Ai,G.,et al.;Pharmacokinetics of exendin−4 in Wistar rats;Journal of Chinese Pharmaceutical Sciences;17(2008)6−10)。 In another preferred embodiment, the active polypeptide is exendin-4. In one example, exendin-4 consists of 39 amino acids. Exendin-4 can be produced by recombinant DNA technology using an E. coli bacterial expression system. The in vivo half-life of unmodified exendin-4 is known to be 0.5 hours iv (Ai, G., et al .; Pharmacokinetics of exendin-4 in Wistar rats; Journal of Chinese Pharmaceuticals; 17 (2008) 6-10).
ベカプレルミンはまた、活性ポリペプチドとして選択されてもよい。ベカプレルミンは、局所投与用の組換えヒト血小板由来成長因子(rhPDGF−BB)である。ベカプレルミンは、酵母株サッカロマイセス・セレビシエに血小板由来増殖因子(PDGF)のB鎖の遺伝子を挿入することにより、組換えDNA技術によって生成することができる。ベカプレルミンの一形態は、約25kDの分子量を有し、ジスルフィド結合により共に結合されている2つの同一ポリペプチド鎖で構成されたホモ二量体である。活性ポリペプチドは、組換えDNA技術により大腸菌(E.coli)内で生成されるインターロイキン11(IL−11)の組換え形態であるオプレルベキンで有り得る。一実施形態において、選択された生物活性ポリペプチドは、約19,000ダルトンの分子量を有し、非グリコシル化型である。このポリペプチドは、長さが177個のアミノ酸であり、ネイティブのIL−11の178個のアミノ酸長とは異なり、唯一アミノ末端プロリン残基を欠いており、これはインビトロまたはインビボのいずれかの生物活性における測定可能な差異を生じないことが知られている。未修飾オプレルベキンの終末半減期は約7時間であることが知られている。さらに別の実施形態は、血中グルコースを増加させ、胃腸管の平滑筋を弛緩させるヒトグルカゴンと同一のポリペプチドホルモンのグルカゴンである生物活性ポリペプチドを提供する。グルカゴンは、グルカゴンの遺伝子を添加することによって遺伝子改変された大腸菌の非病原性の特別な実験室株において合成されてもよい。具体的な実施形態において、グルカゴンは、29個のアミノ酸残基を含み、3,483の分子量を有する一本鎖ポリペプチドである。インビボ半減期は、8〜18分の範囲で、短いことが知られている。 Becaprelmin may also be selected as the active polypeptide. Becaprelmin is a recombinant human platelet derived growth factor (rhPDGF-BB) for topical administration. Becaprelmin can be produced by recombinant DNA technology by inserting the B chain gene of platelet-derived growth factor (PDGF) into the yeast strain Saccharomyces cerevisiae. One form of becaprelmin is a homodimer composed of two identical polypeptide chains that have a molecular weight of about 25 kD and are joined together by disulfide bonds. The active polypeptide can be oprelbekin, which is a recombinant form of interleukin 11 (IL-11) produced in E. coli by recombinant DNA technology. In one embodiment, the selected bioactive polypeptide has a molecular weight of about 19,000 daltons and is non-glycosylated. This polypeptide is 177 amino acids in length and, unlike the native IL-11 178 amino acids long, only lacks the amino-terminal proline residue, which can be either in vitro or in vivo. It is known not to produce measurable differences in biological activity. It is known that the terminal half-life of unmodified oprel bekin is about 7 hours. Yet another embodiment provides a bioactive polypeptide that is a glucagon of the same polypeptide hormone as human glucagon that increases blood glucose and relaxes smooth muscle of the gastrointestinal tract. Glucagon may be synthesized in a non-pathogenic special laboratory strain of E. coli that has been genetically modified by adding the glucagon gene. In a specific embodiment, glucagon is a single chain polypeptide comprising 29 amino acid residues and having a molecular weight of 3,483. In vivo half-life is known to be short, ranging from 8 to 18 minutes.
G−CSFは、活性ポリペプチドとしても選択され得る。組換え顆粒球コロニー刺激因子、すなわちG−CSFは、白血球の回復を刺激するために様々な化学療法治療後に使用される。組換えG−CSFの報告された半減期はわずか3.5時間である。 G-CSF can also be selected as an active polypeptide. Recombinant granulocyte colony stimulating factor, G-CSF, is used after various chemotherapy treatments to stimulate leukocyte recovery. The reported half-life of recombinant G-CSF is only 3.5 hours.
一実施形態において、生物活性ポリペプチドは、インターフェロンα(IFNα)であり得る。化学的にPEG修飾されたインターフェロンアルファ2aは、C型肝炎の治療に対して臨床的に有効である。このPEG化タンパク質は週1回の注射を必要とし、より長い半減期を有する徐放製剤が望ましい。 In one embodiment, the bioactive polypeptide can be interferon alpha (IFNα). Chemically PEG-modified interferon alpha 2a is clinically effective for the treatment of hepatitis C. This PEGylated protein requires weekly injections and a sustained release formulation with a longer half-life is desirable.
さらなる細胞性タンパク質には、以下のものが含まれるが、これらに限定されない:VEGF、VEGF−R1、VEGF−R2、VEGF−R3、Her−1、Her−2、Her−3、EGF−1、EGF−2、EGF−3、Alpha3、cMet、ICOS、CD40L、LFA−1、c−Met、ICOS、LFA−1、IL−6、B7.1、B7.2、OX40、IL−1b、TACI、IgE、BAFF、またはBLys、TPO−R、CD19、CD20、CD22、CD33、CD28、IL−1−R1、TNFα、TRAIL−R1、補体受容体1、FGFa、オステオポンチン、ビトロネクチン、エフリンA1〜A5、エフリンB1〜B3、α−2−マクログロブリン、CCL1、CCL2、CCL3、CCL4、CCL5、CCL6、CCL7、CXCL8、CXCL9、CXCL10、CXCL11、CXCL12、CCL13、CCL14、CCL15、CXCL16、CCL16、CCL17、CCL18、CCL19、CCL20、CCL21、CCL22、PDGF、TGFb、GMCSF、SCF、p40(IL12/IL23)、IL1b、IL1a、IL1ra、IL2、IL3、IL4、IL5、IL6、IL8、IL10、IL12、IL15、IL23、Fas、FasL、Flt3リガンド、41BB、ACE、ACE−2、KGF、FGF−7、SCF、ネトリン1、ネトリン2、IFNa、IFNb、IFNg、カスパーゼ2、カスパーゼ3、カスパーゼ7、カスパーゼ8、カスパーゼ10、ADAMS1、ADAMS5、ADAM8、ADAM9、ADAM15、TS1、TS5、アディポネクチン、ALCAM、ALK−1、APRIL、アネキシンV、アンジオゲニン、アンフィレグリン、アンジオポエチン−1、アンジオポエチン−2、アンジオポエチン−4、B7−1/CD80、B7−2/CD86、B7−H1、B7−H2、B7−H3、Bcl−2、BACE−1、BAK、BCAM、BDNF、bNGF、bECGF、BMP2、BMP3、BMP4、BMP5、BMP6、BMP7、BMP8、CRP、カドヘリン−6、カドヘリン−8、カドヘリン−11、カテプシンA、カテプシンB、カテプシンC、カテプシンD、カテプシンE、カテプシンL、カテプシンS、カテプシンV、カテプシンX、CD11a/LFA−1、LFA−3、GP2b3a、GH受容体、RSV Fタンパク質、IL−23(p40、p19)、IL−12、CD80、CD86、CD28、CTLA−4、a4P1、a4137、TNF/リンフォトキシン、IgE、CD3、CD20、IL−6、IL−6R、BLYS/BAFF、IL−2R、HER2、EGFR、CD33、CD52、ジゴキシン、Rho(D)、水痘、肝炎、CMV、破傷風、ワクシニア、抗毒素、ボツリヌス、Trail−R1、Trail−R2、cMet、TNF−Rファミリー、例えば、LA NGF−R、CD27、CD30、CD40、CD95、リンフォトキシンa/b受容体、Wsl−1、TL1A/TNFSF15、BAFF、BAFF−R/TMFRSF13C、TRAILR2/TNFRSF10B、TRAILR2/TNFRSF10B、Fas/TNFRSF6 CD27/TNFRSF7、DR3/TNFRSF25、HVEM/TNFRSF14、TROY/TNFRSF19、CD40リガンド/TNFSF5、BCMA/TNFRSF17、CD30/TNFRSF8、LIGHT/TNFSF14、4−1BB/TNFRSF9、CD40/TNFRSF5、GITR/TNFRSF18、オステオプロテゲリン/TNFRSF11B、RANK/TNFRSF11A、TRAIL R3/TMFRSF10C、TRAIL/TNFSF10、TRANCE/RANK L/TNFSF11、4−1BBリガンド/TNFSF9、TWEAK/TNFSF12、CD40リガンド/TNFSFS、Fasリガンド/TNFSF6、RELT/TNFRSF19L、APRIL/TNFSF13、DcR3/TNFRSF6B、TNFR1/TNFRSF1A、TRAIL R1/TNFRSF10A、TRAIL R4/TNFRSF10D、CD30リガンド/TNFSF8、GITRリガンド/TNFSF18、TNFSF18、TAC1/TFRSF13B、NGF R/TNFRSF16、OX40リガンド/TNFSF4、TRAIL R2/TNFRSF10B、TRAIL R3/TNFRSF10C、TWEAKR/TNFRSF12、BAFF/BLyS/TNFSF13、DR6/TNFRSF21、TNF−α/TNFSFA1、Pro−TNF−α/TNFSF1A、リンフォトキシンベータR/TNFRSF3、リンフォトキシンベータR(LTbR)/Fcキメラ、TNF R1/TNFRSF1A、TNF−beta/TNFSF1B、PGRP−S、TNF R1/TNFRSF1A、TNF RII/TNFRSF1B、EDA−A2、TNF−アルファ/TNFSF1A、EDAR、XEDAR、TNF R1/TNFRSF1A 4EBP1、14−3−3ゼータ、53BP1、2B4/SLAMF4、CCL21/6Ckine、4−1BB/TNFRSF9、8D6A、4−1BBリガンド/TNFSF9,8−オキソ−dG、4−アミノ−1,8−ナフタルイミド、A2B5、アミノペプチダーゼLRAP/ERAP2、A33、アミノペプチダーゼ N/ANPEP、Aag、アミノペプチダーゼP2/XPNPEP2、ABCG2、アミノペプチダーゼP1/XPNPEP1、ACE、アミノペプチダーゼPILS/ARTS1、ACE−2、アムニオンレス(Amnionless)、アクチン、アンフィレグリン、ベータアクチン、AMPKアルファ1/2、アクチビンA、AMPKアルファ1、アクチビンAB、AMPKアルファ2、アクチビンB、AMPKベータ1、アクチビンC、AMPKベータ2、アクチビンRIA/ALK−2、アンドロゲンR/NR3C4、アクチビンRIB/ALK−4、アンジオゲニン、アクチビンRIIA、アンジオポエチン−1、アクチビンRIIB、アンジオポエチン−2、ADAMS、アンジオポエチン−3、ADAM9、アンジオポエチン−4、ADAM10、アンジオポエチン様1、ADAM12、アンジオポエチン様2、ADAM15、アンジオポエチン様3、TACE/ADAM17、アンジオポエチン様4、ADAM19、アンジオポエチン様7/CDT6、ADAM33、アンジオスタチン、ADAMTS4、アネキシンA1/アネキシンI、ADAMTSS、アネキシンA7、ADAMTS1、アネキシンA10、ADAMTSL−1/プンクチン(Punctin)、アネキシンV、アディポネクチン/Acrp30、ANP、AEBSF、APサイト、アグレカン、APAF−1、アグリン、APC、AgRP、APE、AGTR−2、APT、AIF、APLP−1、Akt、APLP−2、Akt1、アポリポタンパク質AI、Akt2、アポリポタンパク質B、Akt3、APP、血清アルブミン、APRIL/TNFSF13、ALCAM、ARC、ALK−1、アルテミン、ALK−7、アリールスルファターゼA/ARSA、アルカリホスファターゼ、ASAH2/N−アシルスフィンゴシンアミドヒドロラーゼ−2、アルファ2u−グロブリン、ASC、アルファ1−酸性糖タンパク質、ASGR1、アルファフェトプロテイン、ASK1、ALS、ATM、アメロブラスチン、ATRIP、AMICA/JAML、オーロラA、AMIGO、オーロラB、AMIGO2、アキシン−1、AMIGO3、Ax1、アミノアシラーゼ/ACY1、アズロシジン/CAP37/HBP、アミノペプチダーゼA/ENPEP、B4GALT1、BIM、B7−1/CD80、6−ビオチン−17−NAD、B7−2/CD86、BLAME/SLAMF8、B7−H1/PD−L1、CXCL13/BLC/BCA−1、B7−H2、BLIMP1、B7−H3、Blk、B7−H4、BMI−1、BACE−1、BMP−1/PCP、BACE−2、BMP−2、Bad、BMP−3、BAFF/TNFSF13B、BMP−3b/GDF−10、BAFF R/TNFRSF13C、BMP−4、Bag−1、BMP−5、BAK、BMP−6、BAMBI/NMA、BMP−7、BARD1、BMP−8、Bax、BMP−9、BCAM、BMP−10、Bcl−10、BMP−15/GDF−9B、Bcl−2、BMPR−IA/ALK−3、Bcl−2関連タンパク質Al、BMPR−IB/ALK−6、Bcl−w、BMPR−II、Bcl−x、BNIP3L、Bcl−xL、BOC、BCMA/TNFRSF17、BOK、BDNF、BPDE、ベンズアミド、ブラキュリー(Brachyury)、共通β鎖、B−Raf、ベータIG−H3、CXCL14/BRAK、ベタセルリン、BRCA1、ベータ−デフェンシン2、BRCA2、BID、BTLA、バイグリカン、Bub−1、Bik様キラータンパク質、c−jun、CD90/Thy1、c−Rel、CD94、CCL6/C10、CD97、Clq R1/CD93、CD151、C1qTNF1、CD160、ClqTNF4、CD163、ClqTNF5、CD164、補体成分C1r、CD200、補体成分C1s、CD200R1、補体成分C2、CD229/SLAMF3、補体成分C3a、CD23/FcイプシロンRII、補体成分C3d、CD2F−10/SLAMF9、補体成分CSa、CDSL、カドヘリン−4/R−カドヘリン、CD69、カドヘリン−6、CDC2、カドヘリン−8、CDC25A、カドヘリン−11、CDC25B、カドヘリン−12、CDCP1、カドヘリン−13、CDO、カドヘリン−17、CDX4、E−カドヘリン、CEACAM−1/CD66a、N−カドヘリン、CEACAM−6、P−カドヘリン、ケルベロス−1、VE−カドヘリン、CFTR、カルビンジンD、cGMP、カルシニューリンA、Chem R23、カルシニューリンB、ケマリン、カルレティキュリン−2、ケモカインサンプラーパック、CaMキナーゼII、キチナーゼ3様1、cAMP、キトトリオシダーゼ/CHIT1、カンナビノイドR1、Chk1、カンナビノイドR2/CB2/CNR2、Chk2、CAR/NR113、CHL−1/L1CAM−2、炭酸脱水酵素I、コリンアセチルトランスフェラーゼ/ChAT、炭酸脱水酵素II、コンドロレクチン、炭酸脱水酵素III、コーディン、炭酸脱水酵素IV、コーディン様1、炭酸脱水酵素Va、コーディン様2、炭酸脱水酵素VB、CINC−1、炭酸脱水酵素VI、CINC−2、炭酸脱水酵素VII、CINC−3、炭酸脱水酵素VIII、クラスピン、炭酸脱水酵素IX、クローディン6、炭酸脱水酵素X、CLC、炭酸脱水酵素XII、CLEC−1、炭酸脱水酵素XIII、CLEC−2、炭酸脱水酵素XIV、CLECSF13/CLEC4F、カルボキシメチルリジン、CLECSF8、カルボキシペプチダーゼA1/CPA1、CLF−1、カルボキシペプチダーゼA2、CL−P1/COLEC12、カルボキシペプチダーゼA4、クラステリン、カルボキシペプチダーゼB1、クラステリン様1、カルボキシペプチダーゼE/CPE、CMG−2、カルボキシペプチダーゼX1、CMV UL146、カルジオトロフィン−1、CMV UL147、カルノシンジペプチダーゼ1、CNP、カロンテ、CNTF、CART、CNTF Rアルファ、カスパーゼ、凝固因子II/トロンビン、カスパーゼ−1、凝固因子III/組織因子、カスパーゼ−2、凝固因子VII、カスパーゼ−3、凝固因子X、カスパーゼ−4、凝固因子XI、カスパーゼ−6、凝固因子XIV/プロテインC、カスパーゼ−7、COCO、カスパーゼ−8、コヒーシン、カスパーゼ−9、コラーゲンI、カスパーゼ−10、コラーゲンII、カスパーゼ−12、コラーゲンIV、カスパーゼ−13、共通γ鎖/IL−2Rガンマ、カスパーゼペプチド阻害剤、COMP/トロンボスポンジン−5、カタラーゼ、補体成分C1rLP、ベータカテニン、補体成分C1qA、カテプシン1、補体成分
C1qC、カテプシン3、補体因子D、カテプシン6、補体因子I、カテプシンA、補体MASP3、カテプシンB、コネキシン43、カテプシンC/DPPI、コンタクチン−1、カテプシンD、コンタクチン−2/TAG1、カテプシンE、コンタクチン−4、カテプシンF、コンタクチン−5、カテプシンH、コリン、カテプシンL、コルヌリン(Cornulin)、カテプシンO、CORS26/C1qTNF、3、カテプシンS、ラット皮質幹細胞、カテプシンV、コルチゾール、カテプシンX/Z/P、COUP−TFI/NR2F1、CBP、COUP−TFII/NR2F2、CC1、COX−1、CCK−AR、COX−2、CCL28、CRACC/SLAMF7、CCR1、C反応性タンパク質、CCR2、クレアチンキナ−ゼ、Muscle/CKMM、CCR3、クレアチニン、CCR4、CREB、CCR5、CREG、CCR6、CRELD1、CCR7、CRELD2、CCR8、CRHBP、CCR9、CRHR−1、CCR10、CRIMl、CD155/PVR、クリプト、CD2、CRISP−2、CD3、CRISP−3、CD4、クロスベインレス(Crossveinless)−2、CD4+/45RA−、CRTAM、CD4+/45RO−、CRTH−2、CD4+/CD62L−/CD44、CRY1、CD4+/CD62L+/CD44、クリプティック(Cryptic)、CD5、CSB/ERCC6、CD6、CCL27/CTACK、CD8、CTGF/CCN2、CD8+/45RA−、CTLA−4、CD8+/45RO−、キュービリン、CD9、CX3CR1、CD14、CXADR、CD27/TNFRSF7、CXCLI6、CD27リガンド/TNFSF7、CXCR3、CD28、CXCR4、CD30/TNFRSF8、CXCR5、CD30リガンド/TNFSF8、CXCR6、CD31/PECAM−l、シクロフィリンA、CD34、Cyr61/CCN1、CD36/SR−B3、シスタチンA、CD38、シスタチンB、CD40/TNFRSF5、シスタチンC、CD40リガンド/TNFSF5、シスタチンD、CD43、シスタチンE/M、CD44、シスタチンF、CD45、シスタチンH、CD46、シスタチンH2、CD47、シスタチンS、CD48/SLAMF2、シスタチンSA、CD55/DAF、シスタチンSN、CD58/LFA−3、シトクロムc、CD59、アポシトクロムc、CD68、ホロシトクロムc、CD72、サイトケラチン8、CD74、サイトケラチン14、CD83、サイトケラチン19、CD84/SLAMF5、サイトニン(Cytonin)、D6、DISP1、DAN、Dkk−1、DANCE、Dkk−2、DARPP−32、Dkk−3、DAX1/NROB1、Dkk−4、DCC、DLEC、DCIR/CLEC4A、DLL1、DCAR、DLL4、DcR3/TNFRSF6B、d−ルシフェリン、DC−SIGN、DNAリガーゼIV、DC−SIGNR/CD299、DNAポリメラーゼベータ、DcTRAIL R1/TNFRSF23、DNAM−1、DcTRAIL R2/TNFRSF22、DNA−PKcs、DDR1、DNER、DDR2、ドーパカルボキシラーゼ/DDC、DEC−205、DPCR−1、デカペンタプレジック、DPP6、デコリン、DPPA4、デクチン1/CLEC7A、DPPA5/ESG1、デクチン−2/CLEC6A、DPPII/QPP/DPP7、DEP−1/CD148、DPPIV7/CD26、デザートヘッジホッグ、DR3/TNFRSF25、デスミン、DR6/TNFRSF21、デスモグレイン−1、DSCAM、デスモグレイン−2、DSCAM−L1、デスモグレイン−3、DSPG3、ディシェベルド(Dishevelled)−1、Dtk、ディシェベルド−3、ダイナミン、EAR2/NR2F6、EphA5、ECE−1、EphA6、ECE−2、EphA7、ECF−L/CHI3L3、EphA8、ECM−1、EphB1、エコチン、EphB2、EDA、EphB3、EDA−A2、EphB4、EDAR、EphB6、EDG−1、エフリン、EDG−5、エフリン−A1、EDG−8、エフリン−A2、eEF−2、エフリン−A3、EGF、エフリン−A4、EGFR、エフリン−A5、EGR1、エフリン−B、EG−VEGF/PK1、エフリン−B1、eIF2アルファ、エフリン−B2、eIF4E、エフリン−B3、Elk−1、エピジェン、EMAP−II、エピモルフィン/シンタキシン2、EMMPRIN/CD147、エピレグリン、CXCL5/ENA、EPR−1/Xa受容体、エンドカン、ErbB2、エンドグリン/CD105、ErbB3、エンドグリカン、ErbB4、エンドヌクレアーゼIII、ERCC1、エンドヌクレアーゼIV、ERCC3、エンドヌクレアーゼV、ERK1/ERK2、エンドヌクレアーゼVIII、ERK1、エンドレペリン/ペルレカン(Perlecan)、ERK2、エンドスタチン、ERK3、エンドセリン−1、ERK5/BMK1、エングレイルド−2、ERRアルファ/NR3B1、EN−RAGE、ERRベータ/NR3B2、エンテロペプチダーゼ/エンテロキナーゼ、ERRガンマ/NR3B3、CCL11/エオタキシン、エリスロポエチン、CCL24/エオタキシン−2、エリスロポエチンR、CCL26/エオタキシン−3、ESAM、EpCAM/TROP−1、ERアルファ/NR3Al、EPCR、ERベータ/NR3A2、Eph、エキソヌクレアーゼIII、EphA1、エキソストシン(Exostosin)様2/EXTL2、EphA2、エキソストシン様3/EXTL3、EphA3、FABP1、FGF−BP、FABP2、FGF R1−4、FABP3、FGF R1、FABP4、FGF R2、FABP5、FGF R3、FABP7、FGF R4、FABP9、FGF R5、補体因子B、Fgr、FADD、FHR5、FAM3A、フィブロネクチン、FAM3B、フィコリン−2、FAM3C、フィコリン−3、FAM3D、FITC、線維芽細胞活性化タンパク質アルファ/FAP、FKBP38、Fas/TNFRSF6、Flap、Fasリガンド/TNFSF6、FLIP、FATP1、FLRG、FATP4、FLRT1、FATP5、FLRT2、FcガンマR1/CD64、FLRT3、FcガンマRIIB/CD32b、Flt−3、FcガンマRIIC/CD32c、Flt−3リガンド、FcガンマRIIA/CD32a、フォリスタチン、FcガンマRIII/CD16、フォリスタチン様1、FcRH1/IRTA5、FosB/G0S3、FcRH2/IRTA4、FoxD3、FcRH4/IRTA1、FoxJ1、FcRH5/IRTA2、FoxP3、Fc受容体様3/CD16−2、Fpg、FEN−1、FPR1、フェチュインA、FPRL1、フェチュインB、FPRL2、酸性FGF、CX3CL1/フラクタルカイン、塩基性FGF、フリズルド−1、FGF−3、フリズルド−2、FGF−4、フリズルド−3、FGF−5、フリズルド−4、FGF−6、フリズルド−5、FGF−8、フリズルド−6、FGF−9、フリズルド−7、FGF−10、フリズルド−8、FGF−11、フリズルド−9、FGF−12、Frk、FGF−13、sFRP−1、FGF−16、sFRP−2、FGF−17、sFRP−3、FGF−19、sFRP−4、FGF−20、フューリン、FGF−21、FXR/NR1H4、FGF−22、Fyn、FGF−23、G9a/EHMT2、GFRアルファ−3/GDNF Rアルファ−3、GABA−A−Rアルファ1、GFRアルファ−4/GDNF Rアルファ−4、GABA−A−Rアルファ2、GITR/TNFRSF18、GABA−A−Rアルファ4、GITRリガンド/TNFSF18、GABA−A−Rアルファ5、GLI−1、GABA−A−Rアルファ6、GLI−2、GABA−A−Rベータ1、GLP/EHMT1、GABA−A−Rベータ2、GLP−1R、GABA−A−Rベータ3、グルカゴン、GABA−A−Rガンマ2、グルコサミン(N−アセチル)−6−スルファターゼ/GNS、GABA−B−R2、GluR1、GAD1/GAD67、GluR2/3、GAD2/GAD65、GluR2、GADD45アルファ、GluR3、GADD45ベータ、Glut1、GADD45ガンマ、Glut2、ガレクチン−1、Glut3、ガレクチン−2、Glut4、ガレクチン−3、GlutS、ガレクチン−3BP、グルタレドキシン1、ガレクチン−4、グリシンR、ガレクチン−7、グリコホリンA、ガレクチン−8、グリピカン2、ガレクチン−9、グリピカン3、GalNAc4S−65T、グリピカン5、GAP−43、グリピカン6、GAPDH、GM−CSF、Gas1、GM−CSF Rアルファ、Gas6、GMF−ベータ、GASP−1/WFIKKNRP、gp130、GASP−2/WFIKKN、グリコーゲンホスホリラーゼBB/GPBB、GATA−1、GPR15、GATA−2、GPR39、GATA−3、GPVI、GATA−4、GR/NR3C1、GATA−5、Gr−1/Ly−6G、GATA−6、グラニュライシン、GBL、グランザイムA、GCNF/NR6A1、グランザイムB、CXCL6/GCP−2、グランザイムD、G−CSF、グランザイムG、G−CSF R、グランザイムH、GDF−1、GRASP、GDF−3 GRB2、GDF−5、グレムリン、GDF−6、GRO、GDF−7、CXCL1/GROアルファ、GDF−8、CXCL2/GROベータ、GDF−9、CXCL3/GROガンマ、GDF−11、成長ホルモン、GDF−15、成長ホルモンR、GDNF、GRP75/HSPA9B、GFAP、GSK−3アルファ/ベータ、GFI−1、GSK−3アルファ、GFRアルファ−1/GDNF Rアルファ−1、GSK−3ベータ、GFRアルファ−2/GDNF Rアルファ−2、EGN1T、H2AX、ヒスチジン、H60、HM74A、HAI−1、HMGA2、HAI−2、HMGB1、HAI−2A、TCF−2/HNF−1ベータ、HAI−2B、HNF−3ベータ/FoxA2、HAND1、HNF−4アルファ/NR2A1、HAPLN1、HNF−4ガンマ/NR2A2、気道トリプシン様プロテアーゼ/HAT、HO−1/HMOX1/HSP32、HB−EGF、HO−2/HMOX2、CCL14a/HCC、HPRG、CCL14b/HCC−3、Hrk、CCL16/HCC−4、HRP−1、アルファHCG、HS6ST2、Hck、HSD−1、HCR/CRAM−A/B、HSD−2、HDGF、HSP10/EPF、ヘモグロビン、HSP27、ヘパソシン(Hepassocin)、HSP60、HES−1、HSP70、HES−4、HSP90、HGF、HTRA/プロテアーゼDo、HGFアクチベータ、HTRA1/PRSS11、HGF R、HTRA2/Omi、HIF−1アルファ、FVEM/TNFRSF14、HIF−2アルファ、ヒアルロナン、HIN−1/セクレトグロブリン(Secretoglobulin)3A1、4−ヒドロキシノネナール、Hip、CCL1/1−309/TCA−3、IL−10、cIAP(pan)、IL−10Rアルファ、cIAP−1/HIAP−2、IL−10Rベータ、cIAP−2/HIAP−1、IL−11、IBSP//シアロタンパク質II、IL−11Rアルファ、ICAM−1/CD54、IL−12、ICAM−2/CD102、IL−12/IL−23 p40、ICAM−3/CD50、IL−12Rベータ1、ICAM−5、IL−12Rベータ2、ICAT、IL−13、ICOS、IL−13Rアルファ1、イズロン酸−2−スルファターゼ/IDS、IL−13Rアルファ2、IFN、IL−15、IFN−アルファ、IL−15Rアルファ、IFN−アルファ1、IL−16、IFN−アルファ2、IL−17、IFN−アルファ4b、IL−17R、IFN−アルファA、IL−1
7、RCC、IFN−アルファB2、IL−17RD、IFN−アルファC、IL−17B、IFN−アルファD、1L−17BR、IFN−アルファF、IL−17C、IFN−αG、IL−17D、IFN−αH2、IL−17E、IFN−アルファI、I−17F、IFN−アルファJ1、IL−18/IL−1F4、IFN−アルファK、IL−18BPa、IFN−アルファWA、IL−18BPc、IFN−アルファ/ベータRI、IL−18BPd、IFN−アルファ/β R2、IL−18Rアルファ/IL−1 R5、IFN−ベータ、IL−18Rベータ/IL−1 R7、IFN−ガンマ、IL−19、IFN−ガンマR1、IL−20、IFN−ガンマR2、IL−20Rアルファ、IFN−オメガ、IL−20Rベータ、IgE、IL−21、IGFBP−1、IL−21R、IGFBP−2、IL−22、IGFBP−3、IL−22R、IGFBP−4、IL−22BP、IGFBP−5、IL−23、IGFBP−6、IL−23R、IGFBP−L1、IL−24、IGFBP−rp1/IGFBP−7、IL−26/AK155、IGFBP−rP10、IL−27、IGF−I、IL−28A、IGF−IR、IL−28B、IGF−II、IL−29/IFN−ラムダ1、IGF−IIR、IL−31、IgG、IL−31RA、IgM、IL−32アルファ、IGSF2、IL−33、IGSF4A/SynCAM、ILT2/CD85j、IGSF4B、ILT3/CD85k、IGSF8、ILT4/CD85d、IgY、ILT5/CD85a、IkBベータ、ILT6/CD85e、IKKアルファ、インディアンヘッジホッグ、IKKイプシロン、INSRR、IKKガンマ、インスリン、IL−1アルファ/IL−1F1、インスリンR/CD220、IL−1ベータ/IL−1F2、プロインスリン、IL−1ra/IL−1F3、インスリシン/IDE、1L−1F5/FIL1デルタ、インテグリンアルファ2/CD49b、IL−1F6/FIL1イプシロン、インテグリンアルファ3/CD49c、IL−1F7/FIL1ゼータ、インテグリンアルファ3ベータ1/VLA−3、IL−1F8/FIL1イータ、インテグリンアルファ4/CD49d、IL−1F9/IL−1Hl、インテグリンアルファ5/CD49e、IL−1F10/IL−1HY2、インテグリンアルファ5ベータ1、IL−1R1、インテグリンアルファ6/CD49f、IL−1 RII、インテグリンアルファ7、IL−1 R3/IL−1 R ACP、インテグリンアルファ9、IL−1 R4/ST2、インテグリンアルファE/CD103、IL−1R6/IL−1Rrp2、インテグリンアルファL/CD11a、IL−1R8、インテグリンアルファLベータ2、IL−1 R9、インテグリンアルファM/CD11b、IL−2、インテグリンアルファMベータ2、IL−2Rアルファ、インテグリンアルファV/CD51、IL−2Rベータ、インテグリンアルファVベータ5、IL−3、インテグリンアルファVベータ3、IL−3Rアルファ、インテグリンアルファVベータ6、IL−3Rベータ、インテグリンアルファX/CD11c、IL−4、インテグリンベータ1/CD29、IL−4R、インテグリンベータ2/CD18、IL−5、インテグリンベータ3/CD61、IL−5Rアルファ、インテグリンベータ5、1L−6、インテグリンベータ6、IL−6R、インテグリンベータ7、IL−7、CXCL10/IP−10/CRG−2、IL−7Rアルファ/CD127、IRAK1、CXCR1/IL−8RA、IRAK4、CXCR2/IL−8RB、IRS−1、CXCL8/IL−8、Islet−1、IL−9、CXCL11/1−TAC、IL−9R、Jagged 1、JAM−4/IGSFS、Jagged 2、JNK、JAM−A、JNK1/JNK2、JAM−B/VE−JAM、JNK1、JAM−C、JNK2、キニノーゲン、カリクレイン3/PSA、キニノスタチン(Kininostatin)、カリクレイン4、KIR/CD158、カリクレイン5、KIR2DL1、カリクレイン6/ニューロシン、KIR2DL3、カリクレイン7、KIR2DL4/CD158d、カリクレイン8/ニューロプシン、KIR2DS4、カリクレイン9、KIR3DL1、血漿カリクレイン/KLKB1、KIR3DL2、カリクレイン10、Kirrel2、カリクレイン11、KLF4、カリクレイン12、KLFS、カリクレイン13、KLF6、カリクレイン14、クロトー(Klotho)、カリクレイン15、クロトーベータ、KC、KOR、Keap1、クレメン−1、Kell、クレメン−2、KGF/FGF−7、LAG−3、LINGO−2、LAIR1、リピン2、LAIR2、リポカリン−1、ラミニンアルファ4、リポカリン−2/NGAL、ラミニンガンマ1,5−リポキシゲナーゼ、ラミニンI、LXRアルファ/NR1H3、ラミニンS、LXRベータ/NR1H2、ラミニン−1、リヴィン(Livin)、ラミニン−5、LIX、LAMP、LMIR1/CD300A、ランジェリン(Langerin)、LMIR2/CD300c、LAR、LMIR3/CD300LF、ラテキシン、LMIRS/CD300LB、ライリン(Layilin)、LMIR6/CD300LE、LBP、LMO2、LDL R、LOX−1/SR−E1、LECT2、LRH−1/NR5A2、LEDGF、LRIG1、レフティ、LRIG3、レフティ−1、LRP−1、レフティ−A、LRP−6、レグマイン、LSECtin/CLEC4G、レプチン、ルミカン、レプチンR、CXCL−15/ラングカイン(Lungkine)、ロイコトリエンB4、XCL1/リンホタクチン、ロイコトリエンB4 R1、リンフォトキシン、LIF、リンフォトキシンベータ/TNFSF3、LIF Rアルファ、リンフォトキシンベータR/TNFRSF3、LIGHT/TNFSF14、Lyn、リミチン、Lyp、LIMPII/SR−B2、リシルオキシダーゼモホログ2、LIN−28、LYVE−1、LINGO−1、アルファ2−マクログロブリン、CXCL9/MIG、MAD2L1、ミメカン(Mimecan)、MAdCAM−1、ミンジン、MafB、ミネラルコルチコイドR/NR3C2、MafF、CCL3L1/MIP−1アルファ アイソフォームLD78ベータ、MafG、CCL3/MIP−1アルファ、MafK、CCL4L1/LAG−1、MAG/Siglec−4−a、CCL4/MIP−1ベータ、MANF、CCL15/MIP−1デルタ、MAP2、CCL9/10/MIP−1ガンマ、MAPK、MIP−2、マラプシン/パンクレアシン(Marapsin/Pancreasin)、CCL19/MIP−3ベータ、MARCKS、CCL20/MIP−3アルファ、MARCO、MIP−I、Mash1、MIP−II、マトリリン−2、MIP−III、マトリリン−3、MIS/AMH、マトリリン−4、MIS R11、マトリプターゼ/ST14、MIXL1、MBL、MKK3/MKK6、MBL−2、MKK3、メラノコルチン3R/MC3R、MKK4、MCAM/CD146、MKK6、MCK−2、MKK7、Mcl−1、MKP−3、MCP−6、MLH−1、CCL2/MCP−1、MLK4アルファ、MCP−11、MMP、CCL8/MCP−2、MMP−1、CCL7/MCP−3/MARC、MMP−2、CCL13/MCP−4、MMP−3、CCL12/MCP−5、MMP−7、M−CSF、MMP−8、M−CSF R、MMP−9、MCV−タイプII、MMP−10、MD−1、MMP−11、MD−2、MMP−12、CCL22/MDC、MMP−13、MDL−1/CLECSA、MMP−14、MDM2、MMP−15、MEA−1、MMP−16/MT3−MMP、MEK1/ΜΕΚ2、MMP−24/MT5−MMP、MEK1、MMP−25/MT6−MMP、MEK2、MMP−26、メルシン、MMR、MEPE、MOG、メプリンアルファ、CCL23/MPIF−1、メプリンベータ、M−Ras/R−Ras3、Mer、Mrell、メソテリン、MRP1、メテオリン、MSK1/MSK2、メチオニンアミノペプチダーゼ1、MSK1、メチオニンアミノペプチダーゼ、MSK2、メチオニンアミノペプチダーゼ2、MSP、MFG−E8、MSP R/Ron、MFRP、Mug、MgcRacGAP、MULT−1、MGL2、ムサシ−1、MGMT、ムサシ−2、MIA、MuSK、MICA、MutY DNAグリコシラーゼ、MICB、MyD88、MICL/CLEC12A、ミエロペルオキシダーゼ、ベータ2ミクログロブリン、ミオカルディン、ミッドカイン、ミオシリン、MIF、ミオグロビン、NAIP NGFI−Bガンマ/NR4A3、Nanog、NgR2/NgRHl、CXCL7/NAP−2、NgR3/NgRH2、Nbs1、ニドジェン−1/エンタクチン、NCAM−1/CD56、ニドジェン−2、NCAM−L1、一酸化窒素、ネクチン−1、ニトロチロシン、ネクチン−2/CD112、NKG2A、ネクチン−3、NKG2C、ネクチン−4、NKG2D、ネオゲニン、NKp30、ネプリライシン/CD10、NKp44、ネプリライシン−2/MMEL1/MMEL2、NKp46/NCR1、ネスチン、NKp80/KLRF1、NETO2、NKX2.5、ネトリン−1、NMDAR、NR1サブユニット、ネトリン−2、NMDAR、NR2Aサブユニット、ネトリン−4、NMDAR、NR2Bサブユニット、ネトリン−Gla、NMDAR、NR2Cサブユニット、ネトリン−G2a、N−Me−6,7−diOH−TIQ、ニューレグリン−1/NRG1、ノダル(Nodal)、ニューレグリン−3/NRG3、ノギン、ニューリチン、Nogo受容体、ニューロD1(NeuroD1)、Nogo−A、ニューロファシン、NOMO、ニューロゲニン−1、ノープ(Nope)、ニューロゲニン−2、ノリン(Norrin)、ニューロゲニン−3、eNOS、ニューロリシン、iNOS、ニューロフィシンII、nNOS、ニューロピリン−1、ノッチ−1、ニューロピリン−2、ノッチ−2、ニューロポエチン、ノッチ−3、ニューロトリミン、ノッチ−4、ニュールツリン、NOV/CCN3、NFAM1、NRAGE、NF−H、NrCAM、NFkB1、NRL、NFkB2、NT−3、NF−L、NT−4、NF−M、NTB−A/SLAMF6、NG2/MCSP、NTH1、NGF R/TNFRSF16、ヌクレオステミン、ベータ−NGF、Nurr−1/NR4A2、NGFI−Bアルファ/NR4A1、OAS2、オレキシンB、OBCAM、OSCAR、OCAM、OSF−2/ペリオスチン、OCIL/CLEC2d、オンコスタチンM/OSM、OCILRP2/CLEC21、OSM Rベータ、Oct−3/4、オステオアクチビン/GPNMB、OGG1、オステオアドヘリン、オリゴ1、オリゴ2、オリゴ3、オステオカルシン、Olig1、オステオクリン、Olig2、オステオポンチン、Olig3、オステオプロテゲリン/TNFRSF11B、オリゴデンドロサイトマーカー01、Otx2、オリゴデンドロサイトマーカー04、OV−6、OMgp、OX40/TNFRSF4、オプチチン(Opticin)、OX40リガンド/TNFSF4、オレキシンA、OAS2、オレキシンB、OBCAM、OSCAR、OCAM、OSF−2/ペリオスチン、OCIL/CLEC2d、オンコスタチンM/OSM、OCILRP2/CLEC21、OSM Rベータ、Oct−3/4、オステオアクチビン/GPNMB、OGG1、オステオアドヘリン、オリゴ1、オリゴ2、オリゴ3、オステオカルシン、Olig1、オステオクリン、Olig2、オステオポンチン、Olig3、オステオプロテゲリン/TNFRSF11B、オリゴデンドロサイトマーカー01、Otx2、オリゴデンドロサイトマーカー04、OV−6、OMgp、OX40/TNFRSF4、オプチシン(O
pticin)、OX40リガンド/TNFSF4、オレキシンA、RACK1、Ret、Rad1、REV−ERBアルファ/NR1D1、Rad17、REV−ERBベータ/NR1D2、Rad51、Rex−1、Rae−1、RGM−A、Rae−1アルファ、RGM−B、Rae−1ベータ、RGM−C、Rae−1デルタ、Rheb、Rae−1イプシロン、リボソ−ムタンパク質S6、Rae−1ガンマ、RIP1、Raf−1、ROBO1、RAGE、ROBO2、Ra1A/Ra1B、ROBO3、Ra1A、ROBO4、Ra1B、ROR/NR1F1−3(pan)、RANK/TNFRSF11A、RORアルファ/NR1F1、CCL5/RANTES、RORガンマ/NR1F3、Rap1A/B、RTK様オーファン受容体1/RORl、RARアルファ/NR1B1、RTK−オーファン受容体2/ROR2、RARベータ/NR1B2、RP105、RARガンマ/NR1B3、RPA2、Ras、RSK(pan)、RBP4、RSK1/RSK2、RECK、RSKl、Reg2/PAP、RSK2、RegI、RSK3、RegII、RSK4、RegIII、R−スポンジン1、Reg Ma、R−スポンジン2、RegIV、R−スポンジン3、レラキシン−1、RUNX1/CBFA2、リラキシン−2、RUNX2/CBFA1、リラキシン−3、RUNX3/CBFA3、RELMアルファ、RXRアルファ/NR2B1、RELMベータ、RXRベータ/NR2B2、RELT/TNFRSF19L、RXRガンマ/NR2B3、レジスチン、S100A10、SLITRK5、S100A8、SLP1、S100A9、SMAC/ディアブロ、S100B、Smad1、STOOP、Smad2、SALL1、Smad3、デルタ−サルコグリカン、Smad4、Sca−1/Ly6、Smad5、SCD−1、Smad7、SCF、Smad8、SCF R/c−kit、SMC1、SCGF、アルファ−平滑筋アクチン、SCL/Tall、SMUG1、SCP3/SYCP3、Snail、CXCL12/SDF−1、ナトリウムカルシウム交換体1、SDNSF/MCFD2、Soggy−1、アルファ−セクレターゼ、ソニック・ヘッジホッグ、ガンマ−セクレターゼ、SまたはCS1、ベータ−セクレターゼ、SまたはCS3、E−セレクチン、ソルチリン、L−セレクチン、SOST、P−セレクチン、SOX1、セマフォリン3A、SOX2、セマフォリン3C、SOX3、セマフォリン3E、SOX7、セマフォリン3F、SOX9、セマフォリン6A、SOX10、セマフォリン6B、SOX17、セマフォリン6C、SOX21、セマフォリン6D、SPARC、セマフォリン7A、SPARC様1、セパラーゼ、SP−D、セリン/スレオニンホスファターゼ基質I、スピネシン、セルピンA1、F−スポンジン、セルピンA3、SR−AI/MSR、セルピンA4/カリスタチン、Src、セルピンA5/プロテインC阻害剤、SREC−I/SR−F1、セルピンA8/アンジオテンシノーゲン、SREC−II、セルピンB5、SSEA−1、セルピンC1/アンチトロンビン−III、SSEA−3、セルピンD1/ヘパリン補因子II、SSEA−4、セルピンE1/PAI−1、ST7/LRP12、セルピンE2、スタビリン−1、セルピンF1、スタビリン−2、セルピンF2、スタニオカルシン1、セルピンG1/C1阻害剤、スタニオカルシン2、セルピン12、STAT1、血清アミロイドA1、STAT2、SF−1/NR5A1、STAT3、SGK、STAT4、SHBG、STAT5a/b、SHIP、STAT5a、SHP/NROB2、STAT5b、SHP−1、STAT6、SHP−2、VE−スタチン、SIGIRR、Stella/Dppa3、シグレック−2/CD22、STRO−1、シグレック−3/CD33、サブスタンスP、シグレック−5、スルファミダーゼ/SGSH、シグレック−6、スルファターゼ変更因子1/SUMFl、シグレック−7、スルファターゼ変更因子2/SUMF2、シグレック−9、SUMO1、シグレック−10、SUMO2/3/4、シグレック−11、SUMO3、シグレック−F、スーパーオキシドジスムターゼ、SIGNR1/CD209、スーパーオキシドジスムターゼ−1/Cu−Zn SOD、SIGNR4、スーパーオキシドジスムターゼ2/Mn−SOD、SIRPベータ1、スーパーオキシドジスムターゼ−3/EC−SOD、SKI、サバイビン、SLAM/CD150、シナプシンI、スリーピングビューティートランスポサーゼ(Sleeping Beauty Transposase)、シンデカン−1/CD138、Slit3、シンデカン−2、SLITRK1、シンデカン−3、SLITRK2、シンデカン−4、SLITRK4、TAC1/TNFRSF13B、TMFFF1/トモレグリン−1、TAO2、TMFFF2、TAPP1、TNF−アルファ/TNFSF1A、CCL17/TARC、TNF−ベータ/TNFSF1B、Tau、TNF R1/TNFRSF1A、TC21/R−Ras2、TNF R11/TNFRSF1B、TCAM−1、TOR、TCCR/WSX−1、TP−1、TC−PTP、TP63/TP73L、TDG、TR、CCL25/TECK、TRアルファ/NR1A1、テネイシンC、TRベータ1/NR1A2、テネイシンR、TR2/NR2C1、TER−119、TR4/NR2C2、TERT、TRA−1−85、テスチカン1/SPOCKl、TRADD、テスチカン2/SPOCK2、TRAF−1、テスチカン3/SPOCK3、TRAF−2、TFPI、TRAF−3、TFPI−2、TRAF−4、TGF−アルファ、TRAF−6、TGF−ベータ、TRAIL/TNFSF10、TGF−ベータ1、TRAIL R1/TNFRSF10A、LAP(TGF−ベータ1)、TRAIL R2/TNFRSF10B、潜在型TGF−ベータ1、TRAIL R3/TNFRSF10C、TGF−ベータ1.2、TRAIL R4/TNFRSF10D、TGF−ベータ2、TRANCE/TNFSF11、TGF−ベータ3、TfR(トランスフェリンR)、TGF−ベータ5、アポトランスフェリン、潜在型TGF−ベータbp1、ホロ−トランスフェリン、潜在型TGF−ベータbp2、トラッピン(Trappin)−2/Elafin、潜在型TGF−ベータbp4、TREM−1、TGF−ベータRI/ALK−5、TREM−2、TGF−ベータRII、TREM−3、TGF−ベータRllb、TREML1/TLT−1、TGF−ベータRIII、TRF−1、サーモリシン、TRF−2、チオレドキシン−1、TRH分解エクト酵素/TRHDE、チオレドキシン−2、TRIMS、チオレドキシン80、トリペプチジル−ペプチダーゼI、チオレドキシン様5/TRP14、TrkA、THOP1、TrkB、トロンボモジュリン/CD141、TrkC、トロンボポエチン、TROP−2、トロンボポエチンR、トロポニンIペプチド3、トロンボスポンジン−1、トロポニンT、トロンボスポンジン−2、TROY/TNFRSF19、トロンボスポンジン4、トリプシン1、チモポエチン、トリプシン2/PRSS2、胸腺ケモカイン−1、トリプシン3/PRSS3、Tie−1、トリプターゼ−5/Prss32、Tie−2、トリプターゼアルファ/TPS1、TIM−1/KIM−1/HAVCR、トリプターゼベータ−1/MCPT−7、TIM−2、トリプターゼベータ−2/TPSB2、TIM−3、トリプターゼイプシロン/BSSP−4、TIΜ−4、トリプターゼガンマ−1/TPSG1、TIM−5、トリプトファンヒドロキシラーゼ、TIM−6、TSC22、TIMP−1、TSG、TIMP−2、TSG−6、TIMP−3、TSK、TIMP−4、TSLP、TL1A/TNFSF15、TSLP R、TLR1、TSP50、TLR2、ベータIIIチューブリン、TLR3、TWEAK/TNFSF12、TLR4、TWEAK R/TNFRSF12、TLRS、Tyk2、TLR6、ホスホチロシン、TLR9、チロシンヒドロキシラーゼ、TLX/NR2E1、チロシンホスファターゼ基質I、ユビキチン、UNC5H3、Ugi、UNC5H4、DGRPl、UNG、ULBP−1、uPA、ULBP−2、uPAR、ULBP−3、URB、UNC5H1、UVDE、UNC5H2、バニロイドR1、VEGF R、VASA、VEGF R1/Flt−1、バソヒビン、VEGF R2/KDR/Flk−1、バソリン、VEGF R3/Flt−4、バソスタチン、バーシカン、Vav−1、VGSQ、VCAM−1、VHR、VDR/NR111、ビメンチン、VEGF、ビトロネクチン、VEGF−B、VLDLR、VEGF−C、vWF−A2、VEGF−D、シヌクレイン−アルファ、Ku70、WASP、Wnt−7b、WIF−1、Wnt−8a WISP−1/CCN4、Wnt−8b、WNK1、Wnt−9a、Wnt−1、Wnt−9b、Wnt−3a、Wnt−10a、Wnt−4、Wnt−10b、Wnt−5a、Wnt11、Wnt−5b、wnvNS3、Wnt7a、XCR1、XPE/DDB1、XEDAR、XPE/DDB2、Xg、XPF、XIAP、XPG、XPA、XPV、XPD、XRCC、Yes、YY1、EphA4。
Additional cellular proteins include, but are not limited to: VEGF, VEGF-R1, VEGF-R2, VEGF-R3, Her-1, Her-2, Her-3, EGF-1, EGF-2, EGF-3, Alpha3, cMet, ICOS, CD40L, LFA-1, c-Met, ICOS, LFA-1, IL-6, B7.1, B7.2, OX40, IL-1b, TACI, IgE, BAFF, or BLys, TPO-R, CD19, CD20, CD22, CD33, CD28, IL-1-R1, TNFα, TRAIL-R1, complement receptor 1, FGFa, osteopontin, vitronectin, ephrins A1-A5, Ephrin B1-B3, α-2-macroglobulin, CCL1, CCL2, CCL3, CCL4, CC L5, CCL6, CCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CCL13, CCL14, CCL15, CXCL16, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, PDGF, TGFb, GMCSF, SCF, 40p IL23), IL1b, IL1a, IL1ra, IL2, IL3, IL4, IL5, IL6, IL8, IL10, IL12, IL15, IL23, Fas, FasL, Flt3 ligand, 41BB, ACE, ACE-2, KGF, FGF-7, SCF, netrin 1, netrin 2, IFNa, IFNb, IFNg, caspase 2, caspase 3, caspase 7, caspase 8, caspase 10, ADAMS1, ADAMS5, A AM8, ADAM9, ADAM15, TS1, TS5, adiponectin, ALCAM, ALK-1, APRIL, annexin V, angiogenin, amphiregulin, angiopoietin-1, angiopoietin-2, angiopoietin-4, B7-1 / CD80, B7-2 / CD86, B7-H1, B7-H2, B7-H3, Bcl-2, BACE-1, BAK, BCAM, BDNF, bNGF, bECGF, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8, CRP, cadherin -6, cadherin-8, cadherin-11, cathepsin A, cathepsin B, cathepsin C, cathepsin D, cathepsin E, cathepsin L, cathepsin S, cathepsin V, cathepsin X, CD11a / LFA-1, LFA-3, GP b3a, GH receptor, RSV F protein, IL-23 (p40, p19), IL-12, CD80, CD86, CD28, CTLA-4, a4P1, a4137, TNF / lymphotoxin, IgE, CD3, CD20, IL -6, IL-6R, BLYS / BAFF, IL-2R, HER2, EGFR, CD33, CD52, digoxin, Rho (D), chickenpox, hepatitis, CMV, tetanus, vaccinia, antitoxin, botulinum, Trail-R1, Trail- R2, cMet, TNF-R family such as LA NGF-R, CD27, CD30, CD40, CD95, lymphotoxin a / b receptor, Wsl-1, TL1A / TNFSF15, BAFF, BAFF-R / TMFRSF13C, TRAILR2 / TNFRSF10B, TR ILR2 / TNFRSF10B, Fas / TNFRSF6 CD27 / TNFRSF7, DR3 / TNFRSF25, HVEM / TNFRSF14, TROY / TNFRSF19, CD40 ligand / TNFSF5, BCMA / TNFRSF17, CD30 / TNFRSF14L, CD30 / TNFRSF8L GITR / TNFRSF18, osteoprotegerin / TNFRSF11B, RANK / TNFRSF11A, TRAIL R3 / TMFRSF10C, TRAIL / TNFSF10, TRANCE / RANK L / TNFSF11, NFBB ligand / TNFSF9, TNFSF9, TFBB ligand / TNFSF9 , RE T / TNFRSF19L, APRIL / TNFSF13, DcR3 / TNFRSF6B, TNFR1 / TNFRSF1A, TRAIL R1 / TNFRSF10A, TRAIL R4 / TNFRSF10D, CD30 ligand / TNFSF18, GITR ligand / TNFSF18, GITR ligand / TNFSF18 TNFSF4, TRAIL R2 / TNFRSF10B, TRAIL R3 / TNFRSF10C, TWEAKR / TNFRSF12, BAFF / BLyS / TNFSF13, DR6 / TNFRSF21, TNF-α / TNFSFA1, Pro-TNF-R / FNFR Xin beta R (LTbR) / F c Chimera, TNF R1 / TNFRSF1A, TNF-beta / TNFSF1B, PGRP-S, TNF R1 / TNFRSF1A, TNF RII / TNFRSF1B, EDA-A2, TNF-Alpha / TNFSF1A, EDAR, XEDAR4, TNFR1 3-3 zeta, 53BP1, 2B4 / SLAMF4, CCL21 / 6Ckine, 4-1BB / TNFRSF9, 8D6A, 4-1BB ligand / TNFSF9,8-oxo-dG, 4-amino-1,8-naphthalimide, A2B5, amino Peptidase LRAP / ERAP2, A33, aminopeptidase N / AMPEP, Aag, aminopeptidase P2 / XPNPEP2, ABCG2, aminopeptidase P1 / XPNPEP1, AC , Aminopeptidase PILS / ARTS1, ACE-2, amnionless, actin, amphiregulin, beta actin, AMPK alpha 1/2, activin A, AMPK alpha 1, activin AB, AMPK alpha 2, activin B, AMPK beta 1, activin C, AMPK beta 2, activin RIA / ALK-2, androgen R / NR3C4, activin RIB / ALK-4, angiogenin, activin RIIA, angiopoietin-1, activin RIIB, angiopoietin-2, ADAMS, angiopoietin-3, ADAM9, Angiopoietin-4, ADAM10, Angiopoietin-like 1, ADAM12, Angiopoietin-like 2, ADAM15, Angiopoietin-like 3, TA E / ADAM17, Angiopoietin-like 4, ADAM19, Angiopoietin-like 7 / CDT6, ADAM33, Angiostatin, ADAMTS4, Annexin A1 / Annexin I, ADAMTSS, Annexin A7, ADAMTS1, Annexin A10, ADAMSL-1 / Punchin (Punctin), Annexin V Adiponectin / Acrp30, ANP, AEBSF, AP site, aggrecan, APAF-1, Agrin, APC, AgRP, APE, AGTR-2, APT, AIF, APLP-1, Akt, APLP-2, Akt1, apolipoprotein AI, Akt2, apolipoprotein B, Akt3, APP, serum albumin, APRIL / TNFSF13, ALCAM, ARC, ALK-1, Artemin, ALK- , Arylsulfatase A / ARSA, alkaline phosphatase, ASAH2 / N-acyl sphingosine amide hydrolase-2, alpha 2u-globulin, ASC, alpha 1-acid glycoprotein, ASGR1, alpha fetoprotein, ASK1, ALS, ATM, ameloblastin, ATRIP, AMICA / JAML, Aurora A, AMIGO, Aurora B, AMIGO2, Axin-1, AMIGO3, Ax1, Aminoacylase / ACY1, Azulocidin / CAP37 / HBP, Aminopeptidase A / ENPEP, B4GALT1, BIM, B7-1 / CD80 6-biotin-17-NAD, B7-2 / CD86, BLAME / SLAMF8, B7-H1 / PD-L1, CXCL13 / BLC / BCA-1, B7- H2, BLIMP1, B7-H3, Blk, B7-H4, BMI-1, BACE-1, BMP-1 / PCP, BACE-2, BMP-2, Bad, BMP-3, BAFF / TNFSF13B, BMP-3b / GDF-10, BAFF R / TNFRSF13C, BMP-4, Bag-1, BMP-5, BAK, BMP-6, BAMBI / NMA, BMP-7, BARD1, BMP-8, Bax, BMP-9, BCAM, BMP -10, Bcl-10, BMP-15 / GDF-9B, Bcl-2, BMPR-IA / ALK-3, Bcl-2 related protein Al, BMPR-IB / ALK-6, Bcl-w, BMPR-II, Bcl-x, BNIP3L, Bcl-xL, BOC, BCMA / TNFRSF17, BOK, BDNF, BPDE, Benz Amide, Brachyury, common β chain, B-Raf, beta IG-H3, CXCL14 / BRAK, betacellulin, BRCA1, beta-defensin 2, BRCA2, BID, BTLA, biglycan, Bub-1, Bik-like killer protein , C-jun, CD90 / Thy1, c-Rel, CD94, CCL6 / C10, CD97, Clq R1 / CD93, CD151, C1qTNF1, CD160, ClqTNF4, CD163, ClqTNF5, CD164, complement component C1r, CD200, complement component C1s, CD200R1, complement component C2, CD229 / SLAMF3, complement component C3a, CD23 / Fc epsilon RII, complement component C3d, CD2F-10 / SLAMF9, complement component CSa, CDSL, cadhe -4 / R-cadherin, CD69, cadherin-6, CDC2, cadherin-8, CDC25A, cadherin-11, CDC25B, cadherin-12, CDCP1, cadherin-13, CDO, cadherin-17, CDX4, E-cadherin, CEACAM-1 / CD66a, N-cadherin, CEACAM-6, P-cadherin, Cerberus-1, VE-cadherin, CFTR, calbindin D, cGMP, calcineurin A, Chem R23, calcineurin B, chemarin, calreticulin-2 Chemokine sampler pack, CaM kinase II, chitinase 3-like 1, cAMP, chitotriosidase / CHIT1, cannabinoid R1, Chk1, cannabinoid R2 / CB2 / CNR2, Chk2, CAR / NR11 , CHL-1 / L1CAM-2, carbonic anhydrase I, choline acetyltransferase / ChAT, carbonic anhydrase II, chondrolectin, carbonic anhydrase III, chodin, carbonic anhydrase IV, chodin-like 1, carbonic anhydrase Va, chondin Like 2, carbonic anhydrase VB, CINC-1, carbonic anhydrase VI, CINC-2, carbonic anhydrase VII, CINC-3, carbonic anhydrase VIII, claspin, carbonic anhydrase IX, claudin 6, carbonic anhydrase X, CLC, carbonic anhydrase XII, CLEC-1, carbonic anhydrase XIII, CLEC-2, carbonic anhydrase XIV, CLECSF13 / CLEC4F, carboxymethyllysine, CLECSF8, carboxypeptidase A1 / CPA1, CLF-1, carboxypeptidase A2 , CL-P / COLEC12, carboxypeptidase A4, clusterin, carboxypeptidase B1, clusterin-like 1, carboxypeptidase E / CPE, CMG-2, carboxypeptidase X1, CMV UL146, cardiotrophin-1, CMV UL147, carnosine dipeptidase 1, CNP , Caronte, CNTF, CART, CNTF Ralpha, caspase, coagulation factor II / thrombin, caspase-1, coagulation factor III / tissue factor, caspase-2, coagulation factor VII, caspase-3, coagulation factor X, caspase-4, Coagulation factor XI, caspase-6, coagulation factor XIV / protein C, caspase-7, COCO, caspase-8, cohesin, caspase-9, collagen I, caspase-10, collagen II, casp -12, collagen IV, caspase-13, common γ chain / IL-2R gamma, caspase peptide inhibitor, COMP / thrombospondin-5, catalase, complement component C1rLP, beta catenin, complement component C1qA, cathepsin 1. Complement component
C1qC, cathepsin 3, complement factor D, cathepsin 6, complement factor I, cathepsin A, complement MASP3, cathepsin B, connexin 43, cathepsin C / DPPI, contactin-1, cathepsin D, contactin-2 / TAG1, cathepsin E, contactin-4, cathepsin F, contactin-5, cathepsin H, choline, cathepsin L, cornulin, cathepsin O, CORS26 / C1qTNF 3, cathepsin S, rat cortical stem cells, cathepsin V, cortisol, cathepsin X / Z / P, COUP-TFI / NR2F1, CBP, COUP-TFII / NR2F2, CC1, COX-1, CCK-AR, COX-2, CCL28, CRACC / SLAMF7, CCR1, C-reactive protein, CCR2, Clare Nkinase, Muscle / CKMM, CCR3, Creatinine, CCR4, CREB, CCR5, CREG, CCR6, CRELD1, CCR7, CRELD2, CCR8, CRHBP, CCR9, CRHR-1, CCR10, CRIM1, CD155 / PVR, crypto, CD2, CRISP-2, CD3, CRISP-3, CD4, Crossveinless-2, CD4 + / 45RA-, CRTAM, CD4 + / 45RO-, CRTH-2, CD4 + / CD62L- / CD44, CRY1, CD4 + / CD62L + / CD44, Cryptic, CD5, CSB / ERCC6, CD6, CCL27 / CTACK, CD8, CTGF / CCN 2 , CD8 + / 45RA-, CTLA-4, CD8 + / 45RO-, Cubilin, CD9, CX3CR1, CD14, CXADR, CD27 / TNFRSF7, CXCLI6, CD27 ligand / TNFSF7, CXCR3, CD28, CXCR4, CD30 / TNFRSF8, CXCR5 Ligand / TNFSF8, CXCR6, CD31 / PECAM-1, cyclophilin A, CD34, Cyr61 / CCN1, CD36 / SR-B3, cystatin A, CD38, cystatin B, CD40 / TNFRSF5, cystatin C, CD40 ligand / TNFSF5, cystatin D, CD43, cystatin E / M, CD44, cystatin F, CD45, cystatin H, CD46, cystatin H2, CD47, cystatin S, CD48 / S AMF2, Cystatin SA, CD55 / DAF, Cystatin SN, CD58 / LFA-3, Cytochrome c, CD59, Apocytochrome c, CD68, Horocytochrome c, CD72, Cytokeratin 8, CD74, Cytokeratin 14, CD83, Cytokeratin 19 , CD84 / SLAMF5, Cytonin, D6, DISP1, DAN, Dkk-1, DANCE, Dkk-2, DARPP-32, Dkk-3, DAX1 / NROB1, Dkk-4, DCC, DLEC, DCIR / CLEC4A , DLL1, DCAR, DLL4, DcR3 / TNFRSF6B, d-luciferin, DC-SIGN, DNA ligase IV, DC-SIGNR / CD299, DNA polymerase beta, DcTRAIL R1 / TNFRSF2 DNAM-1, DcTRAIL R2 / TNFRSF22, DNA-PKcs, DDR1, DNER, DDR2, dopacarboxylase / DDC, DEC-205, DPCR-1, Decapentaplegic, DPP6, decorin, DPPA4, dectin1 / CLEC7A, DPPA5 / ESG1, Dectin-2 / CLEC6A, DPPII / QPP / DPP7, DEP-1 / CD148, DPPIV7 / CD26, Desert Hedgehog, DR3 / TNFRSF25, Desmin, DR6 / TNFRSF21, Desmograin-1, DSCAM, Desmoglein-2 DSCAM-L1, Desmoglein-3, DSPG3, Dishveled-1, Dtk, Dishveld-3, Dynamin, EAR2 / NR2F6 EphA5, ECE-1, EphA6, ECE-2, EphA7, ECF-L / CHI3L3, EphA8, ECM-1, EphB1, Ecotin, EphB2, EDA, EphB3, EDA-A2, EphB4, EDAR, EphB6, EDG-1, Ephrin, EDG-5, Ephrin-A1, EDG-8, Ephrin-A2, eEF-2, Ephrin-A3, EGF, Ephrin-A4, EGFR, Ephrin-A5, EGR1, Ephrin-B, EG-VEGF / PK1, Ephrin-B1, eIF2alpha, Ephrin-B2, eIF4E, Ephrin-B3, Elk-1, Epigen, EMAP-II, Epimorphin / Syntaxin 2, EMMPRIN / CD147, Epiregulin, CXCL5 / ENA, EPR-1 / Xa receptor , End cans, rbB2, endoglin / CD105, ErbB3, endoglycan, ErbB4, endonuclease III, ERCC1, endonuclease IV, ERCC3, endonuclease V, ERK1 / ERK2, endonuclease VIII, ERK1, endoreperin / Perlecan, ERK2, endo Statins, ERK3, endothelin-1, ERK5 / BMK1, Engrailed-2, ERRalpha / NR3B1, EN-RAGE, ERRbeta / NR3B2, enteropeptidase / enterokinase, ERRgamma / NR3B3, CCL11 / eotaxin, erythropoietin, CCL24 / eotaxin -2, Erythropoietin R, CCL26 / eotaxin-3, ESAM, EpCAM / TROP-1 , ERalpha / NR3Al, EPCR, ERbeta / NR3A2, Eph, Exonuclease III, EphA1, Exostosin-like 2 / EXTL2, EphA2, Exostosine-like 3 / EXTL3, EphA3, FABP1, FGF-BP, GFBP1, FBP -4, FABP3, FGF R1, FABP4, FGF R2, FABP5, FGF R3, FABP7, FGF R4, FABP9, FGF R5, complement factor B, Fgr, FADD, FHR5, FAM3A, fibronectin, FAM3B, Ficolin-2, FAM3C , Ficolin-3, FAM3D, FITC, fibroblast activation protein alpha / FAP, FKBP38, Fas / TNFRSF6, Flap, Fas ligand / TNFSF6, LIP, FATP1, FLRG, FATP4, FLRT1, FATP5, FLRT2, Fc gamma R1 / CD64, FLRT3, Fc gamma RIIB / CD32b, Flt-3, Fc gamma RIIC / CD32c, Flt-3 ligand, Fc gamma RIIA / CD32a, foli Statins, Fc gamma RIII / CD16, follistatin-like 1, FcRH1 / IRTA5, FosB / G0S3, FcRH2 / IRTA4, FoxD3, FcRH4 / IRTA1, FoxJ1, FcRH5 / IRTA2, FoxP3, Fc receptor-like 3 / CD16-2, Fpg , FEN-1, FPR1, Fetuin A, FPRL1, Fetuin B, FPRL2, acidic FGF, CX3CL1 / fractalkine, basic FGF, Frizzled-1, FGF-3, Rizzled-2, FGF-4, Frizzled-3, FGF-5, Frizzled-4, FGF-6, Frizzled-5, FGF-8, Frizzled-6, FGF-9, Frizzled-7, FGF-10, Frizzled- 8, FGF-11, Frizzled-9, FGF-12, Frk, FGF-13, sFRP-1, FGF-16, sFRP-2, FGF-17, sFRP-3, FGF-19, sFRP-4, FGF- 20, Furin, FGF-21, FXR / NR1H4, FGF-22, Fyn, FGF-23, G9a / EHMT2, GFRalpha-3 / GDNF Ralpha-3, GABA-A-Ralpha1, GFRalpha-4 / GDNF R alpha-4, GABA-A-R alpha 2, GITR / TNFRSF18, GABA-A-R alpha 4, G ITR ligand / TNFSF18, GABA-A-Ralpha5, GLI-1, GABA-A-Ralpha6, GLI-2, GABA-A-Rbeta1, GLP / EHMT1, GABA-A-Rbeta2, GLP -1R, GABA-A-R beta 3, glucagon, GABA-A-R gamma 2, glucosamine (N-acetyl) -6-sulfatase / GNS, GABA-B-R2, GluR1, GAD1 / GAD67, GluR2 / 3, GAD2 / GAD65, GluR2, GADD45 alpha, GluR3, GADD45 beta, Glut1, GADD45 gamma, Glut2, galectin-1, Glut3, galectin-2, Glut4, galectin-3, GlutS, galectin-3BP, glutaredoxin-1, galectin-4, Guri R, Galectin-7, Glycophorin A, Galectin-8, Glypican 2, Galectin-9, Glypican 3, GalNAc4S-65T, Glypican 5, GAP-43, Glypican 6, GAPDH, GM-CSF, Gas1, GM-CSF R Alpha, Gas6, GMF-beta, GASP-1 / WFIKKNRP, gp130, GASP-2 / WFIKKKN, glycogen phosphorylase BB / GPBB, GATA-1, GPR15, GATA-2, GPR39, GATA-3, GPVI, GATA-4, GR / NR3C1, GATA-5, Gr-1 / Ly-6G, GATA-6, granulysin, GBL, Granzyme A, GCNF / NR6A1, Granzyme B, CXCL6 / GCP-2, Granzyme D, G-CSF, Granza G, G-CSF R, Granzyme H, GDF-1, GRASP, GDF-3 GRB2, GDF-5, Gremlin, GDF-6, GRO, GDF-7, CXCL1 / GROalpha, GDF-8, CXCL2 / GRO Beta, GDF-9, CXCL3 / GRO gamma, GDF-11, growth hormone, GDF-15, growth hormone R, GDNF, GRP75 / HSPA9B, GFAP, GSK-3alpha / beta, GFI-1, GSK-3alpha, GFRalpha-1 / GDNF Ralpha-1, GSK-3beta, GFRalpha-2 / GDNF Ralpha-2, EGN1T, H2AX, histidine, H60, HM74A, HAI-1, HMGA2, HAI-2, HMGB1, HAI -2A, TCF-2 / HNF-1 beta, HAI 2B, HNF-3 beta / FoxA2, HAND1, HNF-4 alpha / NR2A1, HAPLN1, HNF-4 gamma / NR2A2, airway trypsin-like protease / HAT, HO-1 / HMOX1 / HSP32, HB-EGF, HO-2 / HMOX2, CCL14a / HCC, HPRG, CCL14b / HCC-3, Hrk, CCL16 / HCC-4, HRP-1, Alpha HCG, HS6ST2, Hck, HSD-1, HCR / CRAM-A / B, HSD-2, HDGF , HSP10 / EPF, hemoglobin, HSP27, hepasocin, HSP60, HES-1, HSP70, HES-4, HSP90, HGF, HTRA / protease Do, HGF activator, HTRA1 / PRSS11, HGF R HTRA2 / Omi, HIF-1alpha, FVEM / TNFRSF14, HIF-2alpha, hyaluronan, HIN-1 / Secretoglobulin 3A1, 4-hydroxynonenal, Hip, CCL1 / 1-309 / TCA-3, IL- 10, cIAP (pan), IL-10Ralpha, cIAP-1 / HIAP-2, IL-10Rbeta, cIAP-2 / HIAP-1, IL-11, IBSP // Sialoprotein II, IL-11Ralpha, ICAM -1 / CD54, IL-12, ICAM-2 / CD102, IL-12 / IL-23 p40, ICAM-3 / CD50, IL-12Rbeta1, ICAM-5, IL-12Rbeta2, ICAT, IL- 13, ICOS, IL-13R Alf 1, iduronic acid-2-sulfatase / IDS, IL-13Ralpha2, IFN, IL-15, IFN-alpha, IL-15Ralpha, IFN-alpha1, IL-16, IFN-alpha2, IL-17, IFN-alpha 4b, IL-17R, IFN-alpha A, IL-1
7, RCC, IFN-alpha B2, IL-17RD, IFN-alpha C, IL-17B, IFN-alpha D, 1L-17BR, IFN-alpha F, IL-17C, IFN-αG, IL-17D, IFN- αH2, IL-17E, IFN-alpha I, I-17F, IFN-alpha J1, IL-18 / IL-1F4, IFN-alpha K, IL-18BPa, IFN-alpha WA, IL-18BPc, IFN-alpha / Beta RI, IL-18BPd, IFN-alpha / β R2, IL-18R alpha / IL-1 R5, IFN-beta, IL-18R beta / IL-1 R7, IFN-gamma, IL-19, IFN-gamma R1 IL-20, IFN-gamma R2, IL-20Ralpha, IFN-omega, IL-20Rbeta IgE, IL-21, IGFBP-1, IL-21R, IGFBP-2, IL-22, IGFBP-3, IL-22R, IGFBP-4, IL-22BP, IGFBP-5, IL-23, IGFBP-6, IL-23R, IGFBP-L1, IL-24, IGFBP-rp1 / IGFBP-7, IL-26 / AK155, IGFBP-rP10, IL-27, IGF-I, IL-28A, IGF-IR, IL-28B, IGF-II, IL-29 / IFN-lambda 1, IGF-IIR, IL-31, IgG, IL-31RA, IgM, IL-32alpha, IGSF2, IL-33, IGSF4A / SynCAM, ILT2 / CD85j, IGSF4B, ILT3 / CD85k, IGSF8, ILT4 / CD85d, IgY, ILT5 / CD 5a, IkB beta, ILT6 / CD85e, IKK alpha, Indian hedgehog, IKK epsilon, INSRR, IKK gamma, insulin, IL-1 alpha / IL-1F1, insulin R / CD220, IL-1 beta / IL-1F2, pro Insulin, IL-1ra / IL-1F3, Insulin / IDE, 1L-1F5 / FIL1 Delta, Integrin alpha 2 / CD49b, IL-1F6 / FIL1 Epsilon, Integrin alpha 3 / CD49c, IL-1F7 / FIL1 zeta, Integrin alpha 3 Beta 1 / VLA-3, IL-1F8 / FIL1 eta, integrin alpha 4 / CD49d, IL-1F9 / IL-1Hl, integrin alpha 5 / CD49e, IL-1F10 / IL-1HY2 Integrin alpha 5 beta 1, IL-1R1, Integrin alpha 6 / CD49f, IL-1 RII, Integrin alpha 7, IL-1 R3 / IL-1 R ACP, Integrin alpha 9, IL-1 R4 / ST2, Integrin alpha E / CD103, IL-1R6 / IL-1Rrp2, integrin alpha L / CD11a, IL-1R8, integrin alpha Lbeta2, IL-1 R9, integrin alpha M / CD11b, IL-2, integrin alpha Mbeta2, IL- 2R alpha, integrin alpha V / CD51, IL-2R beta, integrin alpha V beta 5, IL-3, integrin alpha V beta 3, IL-3R alpha, integrin alpha V beta 6, IL-3R beta, in Teglin alpha X / CD11c, IL-4, integrin beta 1 / CD29, IL-4R, integrin beta 2 / CD18, IL-5, integrin beta 3 / CD61, IL-5R alpha, integrin beta 5, 1L-6, Integrin beta 6, IL-6R, Integrin beta 7, IL-7, CXCL10 / IP-10 / CRG-2, IL-7R alpha / CD127, IRAK1, CXCR1 / IL-8RA, IRAK4, CXCR2 / IL-8RB, IRS -1, CXCL8 / IL-8, Isle-1, IL-9, CXCL11 / 1-TAC, IL-9R, Jagged 1, JAM-4 / IGSFS, Jagged 2, JNK, JAM-A, JNK1 / JNK2, JAM -B / VE-JAM, JNK1, JAM-C JNK2, kininogen, kallikrein 3 / PSA, kininostatin, kallikrein 4, KIR / CD158, kallikrein 5, KIR2DL1, kallikrein 6 / neurosin, KIR2DL3, kallikrein 7, KIR2DL4 / CD158d, kallikrein 8 / neuropsin 4 9, KIR3DL1, plasma kallikrein / KLKB1, KIR3DL2, kallikrein 10, Kirrel2, kallikrein 11, KLF4, kallikrein 12, KLFS, kallikrein 13, KLF6, kallikrein 14, Klotho, kallikrein 15, Klotho beta, KC, KOR, KC, KOR, KOR , Clement-1, Kell, Clement-2, KGF / FGF-7, LAG- 3, LINGO-2, LAIR1, Lipin 2, LAIR2, lipocalin-1, laminin alpha 4, lipocalin-2 / NGAL, laminin gamma 1,5-lipoxygenase, laminin I, LXRalpha / NR1H3, laminin S, LXRbeta / NR1H2 Laminin-1, Livin, Laminin-5, LIX, LAMP, LMIR1 / CD300A, Langerin, LMIR2 / CD300c, LAR, LMIR3 / CD300LF, Latexin, LMIRS / CD300LB, Laylin, LMIR6 / CD300LE, LBP, LMO2, LDL R, LOX-1 / SR-E1, LECT2, LRH-1 / NR5A2, LEDGF, LRIG1, Lefty, LRIG3, Lefty 1, LRP-1, Lefty-A, LRP-6, Legumain, LSECtin / CLEC4G, Leptin, Lumican, Leptin R, CXCL-15 / Lungkine, Leukotriene B4, XCL1 / Lymphotactin, Leukotriene B4 R1, Lymphotoxin , LIF, Lymphotoxin beta / TNFSF3, LIF Ralpha, Lymphotoxin beta R / TNFRSF3, LIGHT / TNFSF14, Lyn, Limitin, Lyp, LIMPII / SR-B2, Lysyl oxidase morpholog 2, LIN-28, LYVE- 1, LINGO-1, Alpha 2-macroglobulin, CXCL9 / MIG, MAD2L1, Mimecan, MAdCAM-1, Mindin, MafB, Mineralcorticoid / NR3C2, MafF, CCL3L1 / MIP-1 alpha isoform LD78 beta, MafG, CCL3 / MIP-1 alpha, MafK, CCL4L1 / LAG-1, MAG / Siglec-4-a, CCL4 / MIP-1 beta, MANF, CCL15 / MIP-1 delta, MAP2, CCL9 / 10 / MIP-1 gamma, MAPK, MIP-2, malapsin / pancreasin, CCL19 / MIP-3 beta, MARCKS, CCL20 / MIP-3 alpha , MARCO, MIP-I, Mash1, MIP-II, Matrilin-2, MIP-III, Matrilin-3, MIS / AMH, Matrilin-4, MIS R11, Matriptase / ST14, MIXL1, MBL, M K3 / MKK6, MBL-2, MKK3, melanocortin 3R / MC3R, MKK4, MCAM / CD146, MKK6, MCK-2, MKK7, Mcl-1, MKK-3, MCP-6, MLH-1, CCL2 / MCP-1 , MLK4 alpha, MCP-11, MMP, CCL8 / MCP-2, MMP-1, CCL7 / MCP-3 / MARC, MMP-2, CCL13 / MCP-4, MMP-3, CCL12 / MCP-5, MMP- 7, M-CSF, MMP-8, M-CSF R, MMP-9, MCV-type II, MMP-10, MD-1, MMP-11, MD-2, MMP-12, CCL22 / MDC, MMP- 13, MDL-1 / CLECSA, MMP-14, MDM2, MMP-15, MEA-1, MMP-16 / MT3-MMP, EK1 / ΜΕΚ2, MMP-24 / MT5-MMP, MEK1, MMP-25 / MT6-MMP, MEK2, MMP-26, Mersin, MMR, MEPE, MOG, Meprin Alpha, CCL23 / MPIF-1, Meprin beta, M-Ras / R-Ras3, Mer, Mrell, Mesothelin, MRP1, Meteolin, MSK1 / MSK2, Methionine aminopeptidase 1, MSK1, Methionine aminopeptidase, MSK2, Methionine aminopeptidase 2, MSP, MFG-E8, MSPR R / Ron , MFRP, Mug, MgcRacGAP, MULT-1, MGL2, Musashi-1, MGMT, Musashi-2, MIA, MuSK, MICA, MutY DNA glycosylase, MICB, MyD88, MICL / CLEC12A, Mi Eroperoxidase, beta 2 microglobulin, myocardin, midkine, myosin, MIF, myoglobin, NAIP NGFI-B gamma / NR4A3, Nanog, NgR2 / NgRH1, CXCL7 / NAP-2, NgR3 / NgRH2, Nbs1, nidogen-1 / entactin , NCAM-1 / CD56, Nidogen-2, NCAM-L1, Nitric oxide, Nectin-1, Nitrotyrosine, Nectin-2 / CD112, NKG2A, Nectin-3, NKG2C, Nectin-4, NKG2D, Neogenin, NKp30, Neprilysin / CD10, NKp44, Neprilysin-2 / MMEL1 / MMEL2, NKp46 / NCR1, Nestin, NKp80 / KLRF1, NETO2, NKX2.5, Netrin-1, NM DAR, NR1 subunit, Netrin-2, NMDAR, NR2A subunit, Netrin-4, NMDAR, NR2B subunit, Netrin-Gla, NMDAR, NR2C subunit, Netrin-G2a, N-Me-6,7-diOH- TIQ, Neuregulin-1 / NRG1, Nodal, Neuregulin-3 / NRG3, Noggin, Neuritin, Nogo receptor, NeuroD1 (NeuroD1), Nogo-A, Neurofasin, NOMO, Neurogenin-1, Noop (Nope), Neurogenin-2, Norrin, Neurogenin-3, eNOS, Neurolysin, iNOS, Neuroficin II, nNOS, Neuropilin-1, Notch-1, Neuropilin-2, Notch-2, new Poetin, notch-3, neurotrimine, notch-4, neurturin, NOV / CCN3, NFAM1, NRAGE, NF-H, NrCAM, NFkB1, NRL, NFkB2, NT-3, NF-L, NT-4, NF-M , NTB-A / SLAMF6, NG2 / MCSP, NTH1, NGF R / TNFRSF16, nucleostemin, beta-NGF, Nurr-1 / NR4A2, NGFI-Balpha / NR4A1, OAS2, orexin B, OBCAM, OSCAR, OCAM, OSF-2 / periostin, OCIL / CLEC2d, Oncostatin M / OSM, OCILRP2 / CLEC21, OSM Rbeta, Oct-3 / 4, Osteoactivin / GPNMB, OGG1, Osteoadherin, Oligo 1, Oligo 2, Oligo , Osteocalcin, Olig1, osteocrine, Olig2, osteopontin, Olig3, osteoprotegerin / TNFRSF11B, oligodendrocyte marker 01, Otx2, oligodendrocyte marker 04, OV-6, OMgp, OX40 / TNFRSF4, opticin (Opt40) Ligand / TNFSF4, Orexin A, OAS2, Orexin B, OBCAM, OSCAM, OCAM, OSF-2 / Periostin, OCIL / CLEC2d, Oncostatin M / OSM, OCILRP2 / CLEC21, OSM Rbeta, Oct-3 / 4, Osteoactivin / GPNMB, OGG1, osteoadherin, oligo 1, oligo 2, oligo 3, osteocalcin, Olig1, osteocrine Olig2, osteopontin, Olig3, osteoprotegerin / TNFRSF11B, oligodendrocytes marker 01, Otx2, oligodendrocyte marker 04, OV-6, OMgp, OX40 / TNFRSF4, Opuchishin (O
pticin), OX40 ligand / TNFSF4, orexin A, RACK1, Ret, Rad1, REV-ERB alpha / NR1D1, Rad17, REV-ERB beta / NR1D2, Rad51, Rex-1, Rae-1, RGM-A, Rae-1 Alpha, RGM-B, Rae-1 beta, RGM-C, Rae-1 delta, Rheb, Rae-1 epsilon, ribosomal protein S6, Rae-1 gamma, RIP1, Raf-1, ROBO1, RAGE, ROBO2, Ra1A / Ra1B, ROBO3, Ra1A, ROBO4, Ra1B, ROR / NR1F1-3 (pan), RANK / TNFRSF11A, ROR alpha / NR1F1, CCL5 / RANTES, ROR gamma / NR1F3, Rap1A / B, RTK-like Fan receptor 1 / ROR1, RAR alpha / NR1B1, RTK-orphan receptor 2 / ROR2, RAR beta / NR1B2, RP105, RAR gamma / NR1B3, RPA2, Ras, RSK (pan), RBP4, RSK1 / RSK2, RECK RSK1, Reg2 / PAP, RSK2, RegI, RSK3, RegII, RSK4, RegIII, R-spondin1, RegMa, R-spondin2, RegIV, R-spondin3, relaxin-1, RUNX1 / CBFA2, relaxin-2 , RUNX2 / CBFA1, relaxin-3, RUNX3 / CBFA3, RELMalpha, RXRalpha / NR2B1, RELMbeta, RXRbeta / NR2B2, RELT / TNFRSF19L, RXR gamma / NR2B Resistin, S100A10, SLITRK5, S100A8, SLP1, S100A9, SMAC / Diablo, S100B, Smad1, STOP, Smad2, SALL1, Smad3, Delta-Sarcoglycan, Smad4, Sca-1 / Ly6, Smad-1, Smad-1, SCD-1, Smad SCF, Smad8, SCF R / c-kit, SMC1, SCGF, alpha-smooth muscle actin, SCL / Tall, SMUG1, SCP3 / SYCP3, Snail, CXCL12 / SDF-1, sodium calcium exchanger 1, SDNSF / MCFD2, Soggy -1, alpha-secretase, sonic hedgehog, gamma-secretase, S or CS1, beta-secretase, S or CS3, E-selectin, sorti , L-selectin, SOST, P-selectin, SOX1, semaphorin 3A, SOX2, semaphorin 3C, SOX3, semaphorin 3E, SOX7, semaphorin 3F, SOX9, semaphorin 6A, SOX10, semaphorin 6B, SOX17, Semaphorin 6C, SOX21, Semaphorin 6D, SPARC, Semaphorin 7A, SPARC-like 1, Separase, SP-D, Serine / threonine phosphatase substrate I, Spinesin, Serpin A1, F-spondin, Serpin A3, SR-AI / MSR , Serpin A4 / Calistatin, Src, Serpin A5 / Protein C inhibitor, SREC-I / SR-F1, Serpin A8 / Angiotensinogen, SREC-II, Serpin B5, SSEA-1, Serpin C1 / antitron -III, SSEA-3, serpin D1 / heparin cofactor II, SSEA-4, serpin E1 / PAI-1, ST7 / LRP12, serpin E2, stabilin-1, serpin F1, stabilin-2, serpin F2, stanniocalcin 1 , Serpin G1 / C1 inhibitor, Staniocalcin 2, Serpin 12, STAT1, Serum amyloid A1, STAT2, SF-1 / NR5A1, STAT3, SGK, STAT4, SHBG, STAT5a / b, SHIP, STAT5a, SHP / NROB2, STAT5b, SHP-1, STAT6, SHP-2, VE-statin, SIGIRR, Stella / Dppa3, Siglec-2 / CD22, STRO-1, Siglec-3 / CD33, Substance P, Siglec-5, sulfamidase / SGSH, Siglec-6, sulfatase modifying factor 1 / SUMF1, Siglec-7, sulfatase modifying factor 2 / SUMF2, Siglec-9, SUMO1, Siglec-10, SUMO2 / 3/4, Siglec-11, SUMO3, Siglec-F, Superoxide dismutase, SIGNR1 / CD209, Superoxide dismutase-1 / Cu-Zn SOD, SIGNR4, Superoxide dismutase2 / Mn-SOD, SIRPbeta1, Superoxide dismutase-3 / EC-SOD, SKI, Survivin, SLAM / CD150, Synapsin I, Sleeping Beauty Transposase, Syndecan-1 / CD138, Slit3, Syndeca -2, SLITRK1, Syndecan-3, SLITRK2, Syndecan-4, SLITRK4, TAC1 / TNFRSF13B, TMFFF1 / Tomoregulin-1, TAO2, TMFFF2, TAPP1, TNF-alpha / TNFSF1A, CCL17 / TARC, TNF-Beta / TNSF1, , TNF R1 / TNFRSF1A, TC21 / R-Ras2, TNF R11 / TNFRSF1B, TCAM-1, TOR, TCCR / WSX-1, TP-1, TC-PTP, TP63 / TP73L, TDG, TR, CCL25 / TECK, TR Alpha / NR1A1, Tenascin C, TRbeta1 / NR1A2, Tenascin R, TR2 / NR2C1, TER-119, TR4 / NR2C2, TERT, TRA-1-85, Testica 1 / SPOCK1, TRADD, testican 2 / SPOCK2, TRAF-1, testican 3 / SPOCK3, TRAF-2, TFPI, TRAF-3, TFPI-2, TRAF-4, TGF-alpha, TRAF-6, TGF-beta , TRAIL / TNFSF10, TGF-beta1, TRAIL R1 / TNFRSF10A, LAP (TGF-beta1), TRAIL R2 / TNFRSF10B, latent TGF-beta1, TRAIL R3 / TNFRSF10C, TGF-beta1.2, TRAIL R4 / TNFRSF10D, TGF-beta2, TRANCE / TNFSF11, TGF-beta3, TfR (transferrin R), TGF-beta5, apotransferrin, latent TGF-betabp1, holo-transferry , Latent TGF-beta bp2, Trappin-2 / Elafin, latent TGF-beta bp4, TREM-1, TGF-beta RI / ALK-5, TREM-2, TGF-beta RII, TREM-3 , TGF-betaRllb, TREML1 / TLT-1, TGF-betaRIII, TRF-1, thermolysin, TRF-2, thioredoxin-1, TRH degrading ectoenzyme / TRHDE, thioredoxin-2, TRIMS, thioredoxin 80, tripeptidyl- Peptidase I, thioredoxin-like 5 / TRP14, TrkA, THOP1, TrkB, thrombomodulin / CD141, TrkC, thrombopoietin, TROP-2, thrombopoietin R, troponin I peptide 3, thrombospondin-1, tropo T, thrombospondin-2, TROY / TNFRSF19, thrombospondin 4, trypsin 1, thymopoietin, trypsin 2 / PRSS2, thymus chemokine-1, trypsin 3 / PRSS3, Tie-1, tryptase-5 / Prss32, Tie- 2, tryptase alpha / TPS1, TIM-1 / KIM-1 / HAVCR, tryptase beta-1 / MCPT-7, TIM-2, tryptase beta-2 / TPSB2, TIM-3, tryptase epsilon / BSSP-4, TIΜ- 4, tryptase gamma-1 / TPSG1, TIM-5, tryptophan hydroxylase, TIM-6, TSC22, TIMP-1, TSG, TIMP-2, TSG-6, TIMP-3, TSK, TIMP-4, TSLP, TL1A / TNF SF15, TSLP R, TLR1, TSP50, TLR2, beta III tubulin, TLR3, TWEAK / TNFSF12, TLR4, TWEAK R / TNFRSF12, TLRS, Tyk2, TLR6, phosphotyrosine, TLR9, tyrosine phosphatase, TLX / NR2 I, ubiquitin, UNC5H3, Ugi, UNC5H4, DGRP1, UNG, ULBP-1, uPA, ULBP-2, uPAR, ULBP-3, URB, UNC5H1, UVDE, UNC5H2, Vanilloid R1, VEGF R, VASA, VEGF R1 / TF1 -1, Vasohibin, VEGF R2 / KDR / Flk-1, Vasoline, VEGF R3 / Flt-4, Vasostatin, Versican, Vav-1, VGSQ, V AM-1, VHR, VDR / NR111, vimentin, VEGF, vitronectin, VEGF-B, VLDLR, VEGF-C, vWF-A2, VEGF-D, synuclein-alpha, Ku70, WASP, Wnt-7b, WIF-1, Wnt-8a WISP-1 / CCN4, Wnt-8b, WNK1, Wnt-9a, Wnt-1, Wnt-9b, Wnt-3a, Wnt-10a, Wnt-4, Wnt-10b, Wnt-5a, Wnt11, Wnt -5b, wnvNS3, Wnt7a, XCR1, XPE / DDB1, XEDAR, XPE / DDB2, Xg, XPF, XIAP, XPG, XPA, XPV, XPD, XRCC, Yes, YY1, EphA4.
他の活性ポリペプチドには以下のものが含まれる:BOTOX、ミオブロック、ニューロブロック、ディスポート(または他のボツリヌス神経毒の血清型)、アルグルコシダーゼアルファ、ダプトマイシン、YH−16、コリオゴナドトロピンアルファ、フィルグラスチム、セトロレリクス、インターロイキン−2、アルデスロイキン、テセロイキン、デニロイキンジフチトックス(denileukin diftitox)、インターフェロンアルファ−n3(注射)、インターフェロンアルファ−n1、DL−8234、インターフェロン、サントリ(ガンマ−1a)、インターフェロンガンマ、チモシンアルファ1、タソネルミン、DigiFab、ViperaTAb、EchiTAb、CroFab、ネシリチド、アバタセプト、アレファセプト、レビフ、エプトテルミンアルファ、テリパラチド(骨粗しょう症)、注射用カルシトニン(骨疾患)、カルシトニン(点鼻用、骨粗しょう症)、エタネルセプト、ヘモグロビングルタマー250(ウシ)、ドロトレコギンアルファ、コラゲナーゼ、カルペリチド、組換えヒト上皮細胞増殖因子(局所ゲル、創傷治癒)、DWP−401、ダルベポエチンアルファ、エポエチンオメガ、エポエチンベータ、エポエチンアルファ、デシルジン、レピルジン、ビバリルジン、ノナコグアルファ、モノニン(Mononine)、エプタコグアルファ(活性化)、組換えファクタ−VIII+VWF、Recombinate、組換え第VIII因子、第VIII因子(組換え体)、アルファネート、オクトコグアルファ、第VIII因子、パリフェルミン、インディキナーゼ(Indikinase)、テネクテプラーゼ、アルテプラーゼ、パミテプラーゼ、レテプラーゼ、ナテプラーゼ、モンテプラーゼ、ホリトロピンアルファ、rFSH、hpFSH、ミカファンギン、ペグフィルグラスチム、レノグラスチム、ナルトグラスチム、セルモレリン、グルカゴン、エキセナチド、プラムリンチド、イミグルセラーゼ、ガルスルファーゼ、ロイコトロピン、モルグラモスチム、トリプトレリンアセテート、ヒストレリン(皮下インプラント、ハイドロン)、デスロレリン、ヒストレリン、ナファレリン、ロイプロリド徐放デポー(ATRIGEL)、ロイプロリドインプラント(DUROS)、ゴセレリン、ソマトロピン、ユートロピン、KP−102プログラム、ソマトロピン、ソマトロピン、メカセルミン(成長障害)、エンフビルチド、Org−33408、インスリングラルギン、インスリングルリシン、インスリン(吸入薬)、インスリンリスプロ、インスリンデテミル、インスリン(バッカル剤、RapidMist)、メカセルミンリンファベート(mecasermin rinfabate)、アナキンラ、セルモロイキン、99mTc−アプシタイド(apcitide)注射剤、ミエロピド、ベータセロン、酢酸グラチラマー、ゲポン(Gepon)、サルグラモスチム、オプレルベキン、ヒト白血球由来アルファインターフェロン、ビリブ(Bilive、)インスリン(組換え体)、組換えヒトインスリン、インスリンアスパルト、メカセルミン、ロフェロン−A、インターフェロン−アルファ2、アルファフェロン(Alfaferone)、インターフェロンアルファコン−1、インターフェロンアルファ、アボネックス組換えヒト由来黄体形成ホルモン、ドルナーゼアルファ、トラフェルミン、ジコノチド、タルチレリン、ジボテルミンアルファ、アトシバン、ベカプレルミン、エプチフィバチド、ゼマイラ(Zemaira)、CTC−111、シャンバック(Shanvac)−B、HPVワクチン(四価)、NOV−002、オクトレオチド、ランレオチド、アンセスチム、アガルシダーゼベータ、アガルシダーゼアルファ、ラロニダーゼ、酢酸プレザチド銅(局所用ゲル)、ラスブリカーゼ、ラニビズマブ、アクティミューン、PEG−イントロン、トリコミン(Tricomin)、組換えハウスダストダニアレルギー脱感作注射剤、組換えヒト副甲状腺ホルモン(PTH)1−84(皮下、骨粗しょう症)、エポエチンデルタ、トランスジェニックアンチトロンビンIII、グランジトロピン(Granditropin)、ビトラーゼ(Vitrase)、組換えインスリン、インターフェロンアルファ(経口トローチ剤)、GEM−21S、バプレオチド、イデュルスルファーゼ、オマパトリラート、組換え血清アルブミン、セルトリズマブペゴール、グルカルピダーゼ、ヒト組換えC1エステラーゼ阻害剤(血管性浮腫)、ラノテプラーゼ、組換えヒト成長ホルモン、エンフビルチド(無針注射剤、Biojector 2000)、VGV−1、インターフェロン(アルファ)、ルシナクタント、アビプタジル(吸入用、肺疾患)、イカチバント、エカランチド、オミガナン(omiganan)、オーログラブ(Aurograb)、酢酸ペキシガナン、ADI−PEG−20、LDI−200、デガレリクス、シントレデキン・ベスドトクス(cintredekin besudotox)、FavId、MDX−1379、ISAtx−247、リラグルチド、テリパラチド(骨粗しょう症)、チファコギン(tifacogin)、AA−4500、T4N5リポソームローション、カツマキソマブ、DWP−413、ART−123、クリサリン(Chrysalin)、デスモテプラーゼ、アメジプラーゼ、コリフォリトロピンアルファ、TH−9507、テヅグルチド、ジアミド、DWP−412、成長ホルモン(除放性注射剤)、組換えG−CSF、インスリン(吸入用、AIR)、インスリン(吸入用、Technosphere)、インスリン(吸入用、AERX)、RGN−303、DiaPep277、インターフェロンベータ(C型肝炎ウイルス感染症(HCV))、インターフェロンアルファ−n3(経口用)、ベラタセプト、経皮用インスリンパッチ、AMG−531、MBP−8298、キセレセプト、オペバカン、AIDSVAX、GV−1001、リンホスキャン、ランピルナーゼ、リポキシサン、ルスプルチド、MP52(ベータトリカルシウムホスフェート担体、骨再生)、メラノーマワクチン、シプレウセル−T、CTP−37、インセギア、ビテスペン、ヒトトロンビン(凍結、手術出血)、トロンビン、トランスMID、アリフィメプラーゼ、プリカーゼ、テルリプレシン(静脈内、肝腎臓症候群)、EUR−1008M、組換えFGF−1(注射用、血管疾患)、BDM−E、ロチガプチド、ETC−216、P−113、MBI−594AN、デュラマイシン(吸入用、嚢胞性線維症)、SCV−07、OPI−45、エンドスタチン、アンジオスタチン、ABT−510、ボーマンバーク阻害剤濃縮物、XMP−629、99mTc−Hynic−アネキシンV、カハラリドF、CTCE−9908、テベレリクス(延長放出)、オザレリックス、ロミデプシン、BAY−50−4798、インターロイキン−4、PRX−321、ペプスキャン、イボクタデキン、rhラクトフェリン、TRU−015、IL−21、ATN−161、シレンジチド、アルブフェロン、ビファジックス(Biphasix)、IRX−2、オメガインターフェロン、PCK−3145、CAP−232、パシレオチド、huN901−DM1、卵巣癌免疫療法用ワクチン、SB−249553、オンコバックス−CL、オンコバックス−P、BLP−25、セルバックス−16、多エピトープペプチドメラノーマワクチン(MART−1、gp100、チロシナーゼ)、ネミフィチド、rAAT(吸入用)、rAAT(皮膚科用)、CGRP(吸入用、喘息)、ペグスネルセプト、チモシンベータ−4、プリチデプシン、GTP−200、ラモプラニン、GRASPA、OBI−1、AC−100、サケカルシトニン(経口用、eligen)、カルシトニン(経口用、骨粗鬆症)、エキサモレリン、カプロモレリン、カルデバ、ベラフェルミン、131I−TM−601、KK−220、TP−10、ウラリチド、デペレスタット、ヘマチド、クリサリン(局所用)、rNAPc2、組換え第VIII因子(PEG化リポソーム)、bFGF、PEG化組換えスタフィロキナーゼ変異体、V−10153、ソノリシスプロリーゼ、ニューロバックス、CZEN−002、島細胞新生療法、rGLP−1、BIM−51077、LY−548806、エキセナチド(制御放出、Medisorb)、AVE−0010、GA−GCB、アボレリン、AOD−9604、リナクロチドアセテート、CETi−1、ヘモスパン、VAL(注射用)、急速作用性インスリン(注射用、Viadel)、鼻内インスリン、インスリン(吸入用)、インスリン(経口用、eligen)、組換えメチオニルヒトレプチン、ピトラキンラ皮下注射、湿疹)、ピトラキンラ(吸入用乾燥粉末、喘息)、マルチカイン、RG−1068、MM−093、NBI−6024、AT−001、PI−0824、Org−39141、Cpn10(自己免疫疾患/炎症)、タラクトフェリン(局所用)、rEV−131(眼用)、rEV−131(呼吸疾患)、経口用組換えヒトインスリン(糖尿病)、RPI−78M、オプレルベキン(経口用)、CYT−99007 CTLA4−Ig、DTY−001、バラテグラスト、インターフェロンアルファ−n3(局所用)、IRX−3、RDP−58、タウフェロン、胆汁酸塩刺激リパーゼ、メリスパーゼ、アルカリホスファターゼ、EP−2104R、メラノタン−II、ブレメラノチド、ATL−104、組換えヒトミクロプラスミン、AX−200、SEMAX、ACV−1、Xen−2174、CJC−1008、ジノルフィンA、SI−6603、LAB GHRH、AER−002、BGC−728、マラリアワクチン(ビロソーム、PeviPRO)、ALTU−135、パルボウイルスB19ワクチン、インフルエンザワクチン(組換えノイラミニダーゼ)、マラリア/HBVワクチン、炭疽病ワクチン、Vacc−5q、Vacc−4x、HIVワクチン(経口用)、HPVワクチン、Tatトキソイド、YSPSL、CHS−13340、PTH(1−34)リポソームクリーム(ノバソーム)、オスタボリン−C、PTH類縁体(局所用、乾癬)、MBRI−93.02、MTB72Fワクチン(結核)、MVA−Ag85Aワクチン(結核)、FAR−404、BA−210、組換えペストF1Vワクチン、AG−702、OXSODrol、rBetV1、Der−p1/Der−p2/Der−p7アレルゲン標的化ワクチン(ダストダニアレルギー)、PR1ペプチド抗原(白血病)、突然変異体rasワクチン、HPV−16E7リポペプチドワクチン、ラビリンシンワクチン(腺癌)、CMLワクチン、WT1−ペプチドワクチン(癌)、IDD−5、CDX−110、ペントリス、ノレリン、サイトファブ、P−9808、VT−111、イクロカプチド、テルベルミン(皮膚科、糖尿病性脚部潰瘍)、ルピントリビル、レチキュロース、rGRF、PIA、アルファ−ガラクトシダーゼA、ACE−011、ALTU−140、CGX−1160、アンジオテンシン治療用ワクチン、D−4F、ETC−642、APP−018、rhMBL、SCV−07(経口用、結核)、DRF−7295、ABT−828、ErbB2特異的イムノトキシン(抗癌)、DT3881L−3、TST−10088、PRO−1762、コムボトックス、コレシストキニン−B/ガストリン−受容体結合ペプチド、111In−hEGF、AE−37、トラスツヅマブ−DM1、拮抗剤G、IL−12(組換え)、PM−02734、IMP−321、rhIGF−BP3、BLX−883、CUV−1647(局所用)、L−19系放射線免疫療法剤(癌)、Re−188−P−2045、AMG−386、DC/I540/KLHワクチン(癌)、VX−001、AVE−9633、AC−9301、NY−ESO−1ワクチン(ペプチド)、NA17.A2ペプチド、メラノーマワクチン(パルスド抗原治療薬)、前立腺癌ワクチン、CBP−501、組換えヒトラクトフェリン(ドライアイ)、FX−06、AP−214、WAP−8294A2(注射用)、ACP
−HIP、SUN−11031、ペプチドYY[3−36](肥満、鼻内)、FGLL、アタシセプト、BR3−Fc、BN−003、BA−058、ヒト副甲状腺ホルモン1−34(鼻内、骨粗鬆症)、F−18−CCR1、AT−1001(セリアック病/糖尿病)、JPD−003、PTH(7−34)リポソームクリーム(ノバソーム)、デュラマイシン(眼用、ドライアイ)、CAB−2、CTCE−0214、グリコPEG化エリスロポエチン、EPO−Fc、CNTO−528、AMG−114、JR−013、第XIII因子、アミノカンジン、PN−951、716155、SUN−E7001、TH−0318、BAY−73−7977、テベレリックス(即時放出)、EP−51216、hGH(制御放出、Biosphere)、OGP−I、シフビルチド、TV−4710、ALG−889、Org−41259、rhCC10、F−991、チモペンチン(肺疾患)、r(m)CRP、肝選択的インスリン、スバリン、L19−IL−2融合タンパク質、エラフィン、NMK−150、ALTU−139、EN−122004、rhTPO、トロンボポエチン受容体アゴニスト(血小板減少症)、AL−108、AL−208、神経成長因子拮抗剤(疼痛)、SLV−317、CGX−1007、INNO−105、経口用テリパラチド(eligen)、GEM−OS1、AC−162352、PRX−302、LFn−p24融合ワクチン(テラポア)、EP−1043、小児肺炎ワクチン、マラリアワクチン、髄膜炎細菌グループBワクチン、新生児グループB連鎖球菌ワクチン、炭疽菌ワクチン、HCVワクチン(gpE1+gpE2+MF−59)、中耳炎治療、HCVワクチン(コア抗原+ISCOMATRIX)、hPTH(1−34)(経皮用、ViaDerm)、768974、SYN−101、PGN−0052、アビスクミン、BIM−23190、結核ワクチン、多エピトープチロシナーゼペプチド、癌ワクチン、エンカスチム、APC−8024、GI−5005、ACC−001、TTS−CD3、血管標的化TNF(固形腫瘍)、デスモプレシン(舌下制御放出)、オネルセプト、TP−9201。
Other active polypeptides include: BOTOX, myoblock, neuroblock, export (or other botulinum neurotoxin serotype), alglucosidase alpha, daptomycin, YH-16, choriogonadotropin alpha, Filgrastim, cetrorelix, interleukin-2, aldesleukin, teseleukin, denileukin diftitox, interferon alfa-n3 (injection), interferon alfa-n1, DL-8234, interferon, santri (gamma-1a ), Interferon gamma, thymosin alpha 1, tasonermine, DigiFab, ViperaTAb, EchiTAb, CroFab, nesiritide, abatacept, Alefacept, rebif, eptothermin alfa, teriparatide (osteoporosis), calcitonin for injection (bone disease), calcitonin (nasal nose, osteoporosis), etanercept, hemoglobin glutamer 250 (bovine), drotrecogin alfa, collagenase , Carperitide, recombinant human epidermal growth factor (local gel, wound healing), DWP-401, darbepoetin alfa, epoetin omega, epoetin beta, epoetin alfa, decyldin, repirudine, bivalirudin, nonacog alfa, mononin (Mononene), eptacog alfa (Activation), recombinant factor-VIII + VWF, Recombinate, recombinant factor VIII, factor VIII (recombinant), alphanate, octocog alpha, factor VII Factor, palifermin, indikinase, tenecteplase, alteplase, pamiteplase, reteplase, nateplase, monteplase, follitropin alpha, rFSH, hpFSH, micafungin, pegfilgrastim, lenograstim, nartograstim, celmoregin, celmoregin Pramlintide, imiglucerase, galsulfase, leucotropin, morgramostim, triptorelin acetate, histrelin (subcutaneous implant, hydron), deslorelin, histrelin, nafarelin, leuprolide sustained release depot (ATRIGEL), leuprolide implant (DUROS), goseleline, somatropin , KP-102 program, Soma Lopin, somatropin, mecasermin (growth disorder), enfuvirtide, Org-33408, insulin glargine, insulin gllysine, insulin (inhalant), insulin lispro, insulin detemir, insulin (buccal agent, RapidMist), mecasermin phabate (mecasermin) rinfabate), anakinra, sermoleukin, 99mTc-apcitide injection, myelopide, betaseron, glatiramer acetate, gapon, sargramostim, oprelbequin, human leukocyte-derived alpha interferon, bilive, insulin (recombinant) ), Recombinant human insulin, insulin aspart, mecasermin, loferon-A, interferon Alpha2, alphaferon (Alfaferone), interferon alphacon-1, interferon alpha, avonex recombinant human luteinizing hormone, dornase alpha, trafermin, ziconotide, tartilelin, dibotermin alpha, atosiban, becaprelmine, eptifibatide, zemaira ( Zemaira), CTC-111, Shanvac-B, HPV vaccine (tetravalent), NOV-002, octreotide, lanreotide, ancestim, agarsidase beta, agarsidase alpha, laronidase, prezatide copper acetate (gel for topical use) , Rasburicase, ranibizumab, actimune, PEG-intron, Tricomin, recombinant house dust mite Allergic desensitization injection, recombinant human parathyroid hormone (PTH) 1-84 (subcutaneous, osteoporosis), epoetin delta, transgenic antithrombin III, grungetropin (Grandtropin), vitorase (Vitrase), recombinant insulin , Interferon alpha (oral lozenge), GEM-21S, bapleutide, idursulfase, omapatrilate, recombinant serum albumin, sertolizumab pegol, glucarpidase, human recombinant C1 esterase inhibitor (angioedema) , Lanoteplase, recombinant human growth hormone, enfuvirtide (needleless injection, Biojector 2000), VGV-1, interferon (alpha), lucinactant, aviptadil (for inhalation, lung disease), squid Bunt, Ecarantide, Omiganan, Aurograb, Pexiganan Acetate, ADI-PEG-20, LDI-200, Degarelix, Sintredecine bestotox, FavId, MDX-1379, IS (Osteoporosis), tifacogin, AA-4500, T4N5 liposomal lotion, katsumomab, DWP-413, ART-123, chrysalin, desmoteplase, amediprase, corifolitropin alpha, TH-9507, teguglutidodiamide , DWP-412, growth hormone (sustained injection), recombinant G-CSF, insulin (For inhalation, AIR), insulin (for inhalation, Technosphere), insulin (for inhalation, AERX), RGN-303, DiaPep277, interferon beta (hepatitis C virus infection (HCV)), interferon alpha-n3 (for oral use) ), Belatacept, transdermal insulin patch, AMG-531, MBP-8298, xelecept, opervacan, AIDSVAX, GV-1001, lymphoscan, lampirnase, lipoxysan, rusplutide, MP52 (beta tricalcium phosphate carrier, bone regeneration), Melanoma vaccine, cypreusel-T, CTP-37, inse gear, bitespen, human thrombin (frozen, surgical bleeding), thrombin, trans-MID, arifimeplase, precase, telluripre (Intravenous, hepatorenal syndrome), EUR-1008M, recombinant FGF-1 (for injection, vascular disease), BDM-E, rotigatide, ETC-216, P-113, MBI-594AN, duramycin (for inhalation) Cystic fibrosis), SCV-07, OPI-45, endostatin, angiostatin, ABT-510, Bowman Burke inhibitor concentrate, XMP-629, 99mTc-Hynic-annexin V, Kahalalide F, CTCE-9908, Tiberelix (extended release), Ozarelix, romidepsin, BAY-50-4798, interleukin-4, PRX-321, pepscan, iboctadechin, rh lactoferrin, TRU-015, IL-21, ATN-161, sylenetide, albferon, biphax (Biphas x), IRX-2, omega interferon, PCK-3145, CAP-232, pasireotide, huN901-DM1, vaccine for ovarian cancer immunotherapy, SB-249553, Oncobax-CL, Oncobax-P, BLP-25, cell Bax-16, multi-epitope peptide melanoma vaccine (MART-1, gp100, tyrosinase), nemitide, rAAT (for inhalation), rAAT (for dermatology), CGRP (for inhalation, asthma), pegsnercept, thymosin beta-4, plitidepsin, GTP-200, ramoplanin, GRASPA, OBI-1, AC-100, salmon calcitonin (oral, eigen), calcitonin (oral, osteoporosis), examorelin, capromorelin, caldeba, verafermin, 131I- TM-601, KK-220, TP-10, uralitide, depelstat, hematide, chrysaline (for topical use), rNAPc2, recombinant factor VIII (PEGylated liposome), bFGF, PEGylated recombinant staphylokinase mutant, V -10153, sonolysis prolyse, neurobax, CZEN-002, islet cell neogenesis therapy, rGLP-1, BIM-51077, LY-548806, exenatide (controlled release, Medisorb), AVE-0010, GA-GCB, abolelin, AOD-9604, linaclotide acetate, CETi-1, hemospan, VAL (for injection), fast acting insulin (for injection, Viadel), intranasal insulin, insulin (for inhalation), insulin (for oral, eigen), Recombinant methionyl human Putin, Pitrakinra subcutaneous injection, eczema), Pitrakinra (dry powder for inhalation, asthma), Multikine, RG-1068, MM-093, NBI-6024, AT-001, PI-0824, Org-39141, Cpn10 (autoimmunity Disease / inflammation), talactoferrin (for topical use), rEV-131 (for ophthalmic use), rEV-131 (respiratory disease), oral recombinant human insulin (diabetes), RPI-78M, oprelbequin (for oral use), CYT- 99007 CTLA4-Ig, DTY-001, balategrasto, interferon alpha-n3 (for topical use), IRX-3, RDP-58, tauferon, bile salt-stimulated lipase, merispase, alkaline phosphatase, EP-2104R, melanotan-II, bremeranotide , ATL-104, recombination Human microplasmin, AX-200, SEMAX, ACV-1, Xen-2174, CJC-1008, Dinorphine A, SI-6603, LAB GHRH, AER-002, BGC-728, Malaria vaccine (Vilosome, PeviPRO), ALTU- 135, Parvovirus B19 vaccine, influenza vaccine (recombinant neuraminidase), malaria / HBV vaccine, anthrax vaccine, Vacc-5q, Vacc-4x, HIV vaccine (oral), HPV vaccine, Tat toxoid, YSPSL, CHS-13340 , PTH (1-34) liposome cream (Novasome), Ostaborin-C, PTH analog (Topical, psoriasis), MBRI-93.02, MTB72F vaccine (tuberculosis), MVA-Ag85A vaccine (Tuberculosis), FAR-404, BA-210, recombinant plague F1V vaccine, AG-702, OXSODrol, rBetV1, Der-p1 / Der-p2 / Der-p7 allergen targeted vaccine (dust mite allergy), PR1 peptide antigen (Leukemia), mutant ras vaccine, HPV-16E7 lipopeptide vaccine, labyrincin vaccine (adenocarcinoma), CML vaccine, WT1-peptide vaccine (cancer), IDD-5, CDX-110, Pentris, Norrelin, cytofab , P-9808, VT-111, iclocaptide, terbermine (dermatology, diabetic leg ulcer), lupine trivir, reticulose, rGRF, PIA, alpha-galactosidase A, ACE-011, ALTU-140, CGX-1160, angi Tenshin therapeutic vaccine, D-4F, ETC-642, APP-018, rhMBL, SCV-07 (oral, tuberculosis), DRF-7295, ABT-828, ErbB2-specific immunotoxin (anticancer), DT3881L-3 , TST-10088, PRO-1762, Combotox, cholecystokinin-B / gastrin-receptor binding peptide, 111In-hEGF, AE-37, trastuzumab-DM1, antagonist G, IL-12 (recombinant), PM -02734, IMP-321, rhIGF-BP3, BLX-883, CUV-1647 (for topical use), L-19 series radioimmunotherapy (cancer), Re-188-P-2045, AMG-386, DC / I540 / KLH vaccine (cancer), VX-001, AVE-9633, AC-9301, NY -ESO-1 vaccine (peptide), NA17. A2 peptide, melanoma vaccine (pulsed antigen therapeutic agent), prostate cancer vaccine, CBP-501, recombinant human lactoferrin (dry eye), FX-06, AP-214, WAP-8294A2 (for injection), ACP
-HIP, SUN-11031, peptide YY [3-36] (obesity, intranasal), FGLL, atacicept, BR3-Fc, BN-003, BA-058, human parathyroid hormone 1-34 (intranasal, osteoporosis) , F-18-CCR1, AT-1001 (celiac disease / diabetes), JPD-003, PTH (7-34) liposome cream (Novasome), duramycin (for eyes, dry eye), CAB-2, CTCE-0214 , GlycoPEGylated erythropoietin, EPO-Fc, CNTO-528, AMG-114, JR-013, Factor XIII, aminocandin, PN-951, 716155, SUN-E7001, TH-0318, BAY-73-7777, Tiber Rix (immediate release), EP-51216, hGH (controlled release, Bios here), OGP-I, Schiffvirtide, TV-4710, ALG-889, Org-41259, rhCC10, F-991, thymopentin (lung disease), r (m) CRP, liver-selective insulin, suvaline, L19-IL- 2 fusion proteins, elafin, NMK-150, ALTU-139, EN-122004, rhTPO, thrombopoietin receptor agonist (thrombocytopenia), AL-108, AL-208, nerve growth factor antagonist (pain), SLV-317 , CGX-1007, INNO-105, oral teriparatide (eligen), GEM-OS1, AC-162352, PRX-302, LFn-p24 fusion vaccine (Terapore), EP-1043, pediatric pneumonia vaccine, malaria vaccine, meninges Flame bacteria group B vaccine, Live group B streptococcal vaccine, anthrax vaccine, HCV vaccine (gpE1 + gpE2 + MF-59), otitis media treatment, HCV vaccine (core antigen + ISCOMATRIX), hPTH (1-34) (transdermal, ViaDerm), 768974, SYN-101 , PGN-0052, Abiscumin, BIM-23190, Tuberculosis vaccine, Multi-epitope tyrosinase peptide, Cancer vaccine, Encastim, APC-8024, GI-5005, ACC-001, TTS-CD3, Vascular targeting TNF (solid tumor), Desmopressin (Sublingual controlled release), onercept, TP-9201.
多数の活性タンパク質の核酸およびアミノ酸配列は、当技術分野で公知であり、説明および配列は、ケミカルアブストラクトサービスデータベース(例えば、CASレジストリ)、GenBank、GenPept、Entrezヌクレオチド、Entrezタンパク質、ユニバーサルタンパク質リソース(UniProt)およびGenSeqなどのサブスクリプションデータベース(例えば、ダーウェント)などの公開データベースで利用可能である。ポリヌクレオチド配列は、所与の活性タンパク質(例えば、全長または成熟のいずれか)をコードする野生型ポリヌクレオチド配列であるか、または場合によって、配列は、野生型ポリヌクレオチド配列(例えば、ポリヌクレオチドのDNA配列が、例えば、特定の種における発現のために最適化されている野生型活性タンパク質をコードするポリヌクレオチド;または部位特異的変異体または対立遺伝子変異体などの野生型タンパク質の変異体をコードするポリヌクレオチド)の変異体であってもよい。当技術分野で公知の方法を用いて、かつ/または本明細書に提供され、実施例に詳細に記載されるガイダンスおよび方法と組み合わせて、本発明によって企図される融合タンパク質コンストラクトを作製するために、活性タンパク質の野生型配列もしくはコンセンサスcDNA配列またはコドン最適化変異体を使用することは、十分に当業者の能力内である。 Nucleic acid and amino acid sequences for a number of active proteins are known in the art, and descriptions and sequences can be found in chemical abstract service databases (eg, CAS registry), GenBank, GenPept, Entrez nucleotides, Entrez proteins, Universal protein resources (UniProt ) And subscription databases such as GenSeq (eg Derwent). The polynucleotide sequence is a wild-type polynucleotide sequence that encodes a given active protein (eg, either full-length or mature), or in some cases, the sequence is a wild-type polynucleotide sequence (eg, of a polynucleotide). A polynucleotide that encodes a wild-type active protein whose DNA sequence is optimized for expression in a particular species, for example; or a variant of a wild-type protein such as a site-specific variant or allelic variant The polynucleotide may be a mutant. To create fusion protein constructs contemplated by the present invention using methods known in the art and / or in combination with the guidance and methods provided herein and described in detail in the Examples. It is well within the ability of one skilled in the art to use wild type sequences or consensus cDNA sequences of active proteins, or codon optimized variants.
融合タンパク質の薬物動態特性
本発明は、ムチンポリペプチドドメインに連結されていない治療活性タンパク質と比較して、強化された薬物動態を有する治療活性タンパク質の融合タンパク質であって、本明細書に記載の方法によって組成物に対して決定された最適な用量で使用した場合に、本発明に従ってムチンドメインポリペプチドに連結されていない治療活性タンパク質の同等の用量と比較して、強化された薬物動態を達成することができる融合タンパク質を提供する。本明細書で使用する「同程度の用量」とは、同等の様式で対象に投与される治療活性タンパク質の等モル/kgを有する用量を意味する。融合タンパク質の「同程度の投与量」は、薬剤のより重い重量を表すが、融合タンパク質の用量の中に本質的に同じモル当量の治療活性タンパク質を有するか、かつ/または治療活性タンパク質と比較してほぼ同じモル濃度を有することは、当技術分野では理解されるであろう。
Pharmacokinetic properties of fusion proteins The present invention is a fusion protein of a therapeutically active protein having enhanced pharmacokinetics compared to a therapeutically active protein that is not linked to a mucin polypeptide domain, as described herein. Enhanced pharmacokinetics is achieved when used at the optimal dose determined for the composition by the method compared to an equivalent dose of therapeutically active protein not linked to a mucin domain polypeptide according to the present invention Provided is a fusion protein capable of As used herein, “similar dose” means a dose having equimolar / kg of therapeutically active protein administered to a subject in an equivalent manner. A “similar dose” of a fusion protein represents a heavier weight of the drug, but has essentially the same molar equivalent of therapeutically active protein in the fusion protein dose and / or compared to the therapeutically active protein It will be understood in the art that they have approximately the same molar concentration.
治療活性タンパク質にムチンポリペプチドドメインを連結することによって高めることができる治療活性タンパク質の薬物動態(PK)特性には、半減期、曲線下面積(AUC)、Cmax、Tmax、トラフ/ピーク濃度比、および分布容積が含まれる。PK特性の強化は、暴露の増加による有効性の向上、用量の減少による有害事象の減少、Cmaxの低下、および投与頻度の減少につながり得る。実施例においてより完全に記載するとおり、本発明は、融合タンパク質に連結されていない対応する治療活性タンパク質と比較して、投与された融合タンパク質の半減期を少なくとも約2倍、少なくとも約3倍、少なくとも約4倍、少なくとも約5倍、少なくとも約6倍、少なくとも約7倍、少なくとも約8倍、少なくとも約9倍、少なくとも約10倍、少なくとも約15倍、少なくとも約20倍またはそれ以上長くさせる、治療活性タンパク質に連結されたムチンドメインポリペプチドを含む融合タンパク質を提供する。 The pharmacokinetic (PK) properties of a therapeutically active protein that can be enhanced by linking a mucin polypeptide domain to the therapeutically active protein include half-life, area under the curve (AUC), C max , T max , trough / peak concentration. Ratio and distribution volume are included. Enhanced PK properties can lead to improved efficacy with increased exposure, decreased adverse events with decreased dose, decreased Cmax , and decreased dosing frequency. As described more fully in the Examples, the present invention provides at least about 2 times, at least about 3 times the half-life of the administered fusion protein as compared to the corresponding therapeutically active protein that is not linked to the fusion protein, At least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, at least about 10 times, at least about 15 times, at least about 20 times or more, A fusion protein comprising a mucin domain polypeptide linked to a therapeutically active protein is provided.
同様に、本発明の融合タンパク質は、融合タンパク質に連結されていない対応する治療活性タンパク質と比較して、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約90%、少なくとも約100%、少なくとも約150%、少なくとも約200%、または少なくとも約300%のAUCの増加を有し得る。本発明の融合タンパク質の半減期およびAUCの薬物動態パラメータは、投薬を含む標準的な方法、複数の時間間隔での血液試料の採取、およびELISA、HPLC、ラジオアッセイを用いるタンパク質のアッセイ、または当技術分野で公知のもしくは本明細書に記載の他の方法によって決定することができ、続いて、データの標準的な計算を行い、半減期および他のPKパラメータを導くことができる。 Similarly, a fusion protein of the invention is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90 compared to the corresponding therapeutically active protein not linked to the fusion protein. %, At least about 100%, at least about 150%, at least about 200%, or at least about 300% increase in AUC. The half-life and AUC pharmacokinetic parameters of the fusion proteins of the invention can be determined using standard methods including dosing, collection of blood samples at multiple time intervals, and protein assays using ELISA, HPLC, radioassays, or the like. It can be determined by other methods known in the art or as described herein, followed by standard calculations of the data to derive half-life and other PK parameters.
半減期の増加は、ピーク/トラフ濃度比の減少をもたらし、複数回用量が送達されたときの濃度対時間プロファイルを平滑化する。より一貫した暴露は、有効性の向上だけでなく、高いCmax(超治療濃度(supratherapeutic concentration))によって促進される場合が多い有害事象の減少をもたらすことができる。個々の用量の持続時間の延長は、投与頻度も低減させ、(注射部位反応などの)任意の送達関連有害事象の減少、コンプライアンスの向上、および患者に対する利便性の追加をもたらす。 An increase in half-life results in a decrease in the peak / trough concentration ratio and smoothes the concentration versus time profile when multiple doses are delivered. More consistent exposure can lead to not only increased efficacy, but also reduced adverse events that are often facilitated by high C max (supertherapeutic concentration). Increasing the duration of individual doses also reduces the frequency of administration, resulting in reduced any delivery-related adverse events (such as injection site reactions), increased compliance, and added convenience to the patient.
物理化学特性および医薬特性
治療薬のPK特性を強化することに加えて、ムチンドメインポリペプチドへの融合は、治療活性ペプチドまたはタンパク質の医薬特性または(水溶解度の程度などの)物理化学的特性を向上させるのに有用であり得る。溶解度の向上は、ムチン上の高度に親水性の炭水化物の付加、ならびにアスパラギン酸、グルタミン酸、ヒスチジン、リジン、およびアルギニンなどのイオン化可能な残基をさらに含み得る適切なムチンポリペプチド配列の選択の両方を介して媒介され得る。イオン化可能な残基は、融合タンパク質のpIおよびそれによって特定の製剤中のタンパク質の全電荷の調節をもたらす。
Physicochemical and pharmaceutical properties In addition to enhancing the PK properties of a therapeutic agent, fusion to a mucin domain polypeptide can enhance the pharmaceutical properties or physicochemical properties (such as the degree of water solubility) of a therapeutically active peptide or protein. It can be useful to improve. Improved solubility both adds highly hydrophilic carbohydrates on the mucin and selects an appropriate mucin polypeptide sequence that can further include ionizable residues such as aspartic acid, glutamic acid, histidine, lysine, and arginine. Can be mediated through The ionizable residues result in the modulation of the pI of the fusion protein and thereby the total charge of the protein in a particular formulation.
本発明の融合タンパク質は、所望の特性をもたらす融合タンパク質の物理化学的特性を確認するために、本明細書に記載の方法を使用して、構築し、アッセイすることができる。一実施形態において、ムチンドメインポリペプチドは、融合タンパク質が、融合タンパク質に連結されていない治療活性タンパク質と比較して、融合タンパク質に連結されていない対応する治療活性タンパク質よりも少なくとも約25%、少なくとも約30%、少なくとも約40%、少なくとも約50%、少なくとも約75%、少なくとも約100%、少なくとも約200%、少なくとも約300%、少なくとも約400%、少なくとも約500%、または少なくとも約1000%上回る範囲内にある水溶性を有するように選択される。好ましいムチンドメインポリペプチド配列は、表Iから選択されるムチンドメインポリペプチドと少なくとも80%の配列同一性、約90%、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%、約99%、約100%の配列同一性を有し得る。 The fusion proteins of the invention can be constructed and assayed using the methods described herein to ascertain the physicochemical properties of the fusion protein that provide the desired properties. In one embodiment, the mucin domain polypeptide has at least about 25% at least about a corresponding therapeutically active protein that is not linked to the fusion protein, compared to a therapeutically active protein that is not linked to the fusion protein. About 30%, at least about 40%, at least about 50%, at least about 75%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, or at least about 1000% higher Selected to have water solubility within the range. Preferred mucin domain polypeptide sequences are at least 80% sequence identity, about 90%, about 91%, about 92%, about 93%, about 94%, about 95% with a mucin domain polypeptide selected from Table I , About 96%, about 97%, about 98%, about 99%, about 100% sequence identity.
融合タンパク質の使用
別の態様において、本発明は、治療活性タンパク質によって媒介される疾患、障害または病状において有益な効果を達成するための方法を提供する。本発明は、比較的短い終末半減期および/もしくは最小有効量と最大耐量との間の狭い治療枠を有する治療活性タンパク質の欠点ならびに/または制限に対処する。
Use of Fusion Proteins In another aspect, the present invention provides a method for achieving a beneficial effect in a disease, disorder or condition mediated by a therapeutically active protein. The present invention addresses the shortcomings and / or limitations of therapeutically active proteins that have a relatively short terminal half-life and / or a narrow therapeutic window between the minimum effective and maximum tolerated dose.
一実施形態において、本発明は、対象において有益な効果を達成するための方法であって、治療的または予防的有効量の融合タンパク質を対象へ投与するステップを含む方法を提供する。有効量は、疾患または障害を治療するうえで有益な効果をもたらし得る。場合によっては、有益な効果を達成するための方法は、ムチンドメインポリペプチドに連結されていない治療用タンパク質またはペプチドが、準最適な半減期を示す疾患および疾患カテゴリーについて対象を治療するために、治療有効量の融合タンパク質組成物を投与することを含み得る。他の場合において、有益な効果を達成するための方法は、治療用タンパク質またはペプチドが存在しない疾患および疾患カテゴリーについて対象を治療するために、治療有効量の融合タンパク質組成物を投与することを含み得る。さらに他の場合において、有益な効果を達成するための方法は、治療用タンパク質またはペプチドがそれぞれアゴニストまたはアンタゴニストとして準最適な刺激効果または準最適な阻害効果を示す疾患および疾患カテゴリーについて対象を治療するために、治療有効量の融合タンパク質組成物を投与することを含み得る。 In one embodiment, the present invention provides a method for achieving a beneficial effect in a subject comprising administering to the subject a therapeutically or prophylactically effective amount of the fusion protein. An effective amount can have a beneficial effect in treating the disease or disorder. In some cases, a method for achieving a beneficial effect is to treat a subject for diseases and disease categories in which a therapeutic protein or peptide that is not linked to a mucin domain polypeptide exhibits a sub-optimal half-life. Administering a therapeutically effective amount of the fusion protein composition. In other cases, a method for achieving a beneficial effect comprises administering a therapeutically effective amount of a fusion protein composition to treat a subject for diseases and disease categories in which no therapeutic protein or peptide is present. obtain. In yet other cases, a method for achieving a beneficial effect treats a subject for diseases and disease categories in which the therapeutic protein or peptide exhibits a suboptimal stimulatory effect or suboptimal inhibitory effect, respectively, as an agonist or antagonist. Thus, it can comprise administering a therapeutically effective amount of the fusion protein composition.
本発明の組成物の投与により治療可能な疾患には、癌、炎症性疾患、関節炎、骨粗しょう症、特に肝炎における感染症、細菌感染症、ウイルス感染症、遺伝的疾患、肺疾患、1型糖尿病、2型糖尿病、ホルモン関連疾患、アルツハイマー病、心疾患、心筋梗塞、深部血管血栓症、循環器系疾患、高血圧症、低血圧症、アレルギー、鎮痛、小人症および他の増殖性疾患、中毒、ブロット凝固疾患、先天性免疫系の疾患、塞栓症、創傷治癒、火傷の治癒、クローン病、喘息、潰瘍、敗血症、緑内障、脳血管虚血、呼吸窮迫症候群、角膜潰瘍、腎疾患、糖尿病性足潰瘍、貧血、第IX因子欠損症、第VIII因子欠乏症、第VII因子欠乏、粘膜炎、嚥下障害、血小板障害、肺塞栓症、不妊症、性腺機能低下症、白血球減少、好中球減少症、子宮内膜症、ゴーシェ病、肥満症、リソソーム蓄積症、エイズ、月経前症候群、ターナー症候群、悪液質、筋ジストロフィー、ハンチントン病、大腸炎、SARS、カポジ肉腫、肝臓腫瘍、乳房腫瘍、神経膠腫、非ホジキンリンパ腫、慢性骨髄性白血病、有毛細胞白血病、腎細胞癌、肝腫瘍、リンパ腫、黒色腫、多発性硬化症、カポジ肉腫、乳頭腫ウイルス、肺気腫、気管支炎、歯周病、認知症、分娩、非小細胞肺癌、膵臓腫瘍、前立腺腫瘍、末端肥大症、乾癬、卵巣腫瘍、ファブリー病、リソソーム蓄積症が含まれるが、これらに限定されない。 Diseases that can be treated by administration of the composition of the present invention include cancer, inflammatory diseases, arthritis, osteoporosis, particularly infections in hepatitis, bacterial infections, viral infections, genetic diseases, lung diseases, type 1 Diabetes, type 2 diabetes, hormone-related disease, Alzheimer's disease, heart disease, myocardial infarction, deep vascular thrombosis, cardiovascular disease, hypertension, hypotension, allergy, analgesia, dwarfism and other proliferative diseases, Poisoning, blot coagulation disease, innate immune system disease, embolism, wound healing, burn healing, Crohn's disease, asthma, ulcer, sepsis, glaucoma, cerebrovascular ischemia, respiratory distress syndrome, corneal ulcer, kidney disease, diabetes Sexual foot ulcer, anemia, factor IX deficiency, factor VIII deficiency, factor VII deficiency, mucositis, dysphagia, platelet disorder, pulmonary embolism, infertility, hypogonadism, leukopenia, neutropenia Disease, intrauterine Disease, Gaucher disease, obesity, lysosomal storage disease, AIDS, premenstrual syndrome, Turner syndrome, cachexia, muscular dystrophy, Huntington's disease, colitis, SARS, Kaposi's sarcoma, liver tumor, breast tumor, glioma, non-Hodgkin Lymphoma, chronic myelogenous leukemia, hairy cell leukemia, renal cell carcinoma, liver tumor, lymphoma, melanoma, multiple sclerosis, Kaposi's sarcoma, papilloma virus, emphysema, bronchitis, periodontal disease, dementia, parturition, Non-small cell lung cancer, pancreatic tumor, prostate tumor, acromegaly, psoriasis, ovarian tumor, Fabry disease, lysosomal storage disease include but are not limited to.
一実施形態において、本方法は、同程度の用量で投与される、ムチンドメインポリペプチドに連結されていない治療活性タンパク質を含む医薬組成物の投与によって媒介される効果と比較して、融合タンパク質の治療活性タンパク質によって媒介される少なくとも1つのパラメータ、生理学的条件、または臨床転帰においてより大きな改善をもたらし、ムチンドメインポリペプチドに連結された治療活性タンパク質を含む融合タンパク質および少なくとも1つの薬学的に許容される担体を含む治療有効量の医薬組成物を、それを必要とする対象に投与することを含む。一実施形態において、この医薬組成物は、治療有効用量で投与される。別の実施形態において、この医薬組成物は、投薬期間の長さについて(本明細書で定義される)治療有効用量投与計画を使用して、複数の同時投与または連続投与により投与される。 In one embodiment, the method comprises comparing the effect of the fusion protein compared to the effect mediated by administration of a pharmaceutical composition comprising a therapeutically active protein that is not linked to a mucin domain polypeptide, administered at a comparable dose. A fusion protein comprising a therapeutically active protein linked to a mucin domain polypeptide and at least one pharmaceutically acceptable that results in a greater improvement in at least one parameter, physiological condition, or clinical outcome mediated by the therapeutically active protein Administering a therapeutically effective amount of a pharmaceutical composition comprising a carrier to a subject in need thereof. In one embodiment, the pharmaceutical composition is administered at a therapeutically effective dose. In another embodiment, the pharmaceutical composition is administered by multiple simultaneous or sequential administrations using a therapeutically effective dose regimen (as defined herein) for the length of the dosing period.
延長された半減期などの本明細書に記載されるような融合タンパク質の強化された薬物動態学的パラメータの結果として、ムチンドメインポリペプチドに連結された治療活性タンパク質は、疾患、障害もしくは病状の症状または臨床的異常を予防、治療、緩和、逆転もしくは緩解するか、または治療されている対象の生存を延長するために、ムチンドメインポリペプチドに連結されていない対応する治療活性タンパク質と比較して、長い投与間隔を用いて投与され得る。 As a result of the enhanced pharmacokinetic parameters of the fusion protein as described herein, such as an extended half-life, a therapeutically active protein linked to a mucin domain polypeptide may be of a disease, disorder or condition. To prevent, treat, alleviate, reverse or ameliorate symptoms or clinical abnormalities or prolong the survival of the subject being treated compared to the corresponding therapeutically active protein not linked to a mucin domain polypeptide Can be administered using long dosing intervals.
融合タンパク質の治療有効量は、個体の疾患状態、年齢、性別、および体重、ならびに個体において所望の応答を誘発する抗体または抗体部分の能力などの要因に従って変化し得る。治療有効量はまた、融合タンパク質の任意の毒性もしくは有害な効果を治療的に有益な効果が上回るものでもある。予防有効量は、所望の予防結果を達成するのに要する期間に必要とされる融合タンパク質の量を指す。 A therapeutically effective amount of the fusion protein can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit the desired response in the individual. A therapeutically effective amount is also a therapeutically beneficial effect that exceeds any toxic or deleterious effects of the fusion protein. A prophylactically effective amount refers to the amount of fusion protein required for the time required to achieve the desired prophylactic result.
一実施形態において、治療方法は、本発明の融合ポリペプチドに連結されていない同程度の用量の治療活性タンパク質と比較して、治療活性タンパク質の半減期の増加をもたらす本発明の融合タンパク質を含む治療有効用量の医薬組成物を、それを必要とする対象に投与することを含む。 In one embodiment, the method of treatment comprises a fusion protein of the invention that results in an increased half-life of the therapeutically active protein compared to a comparable dose of therapeutically active protein that is not linked to the fusion polypeptide of the invention. Administering a therapeutically effective dose of the pharmaceutical composition to a subject in need thereof.
別の態様において、本発明は、発現後の化学的カップリングを必要とする半減期延長技術に関連する製造の容易さを向上させ、ネイティブな治療活性タンパク質と比較して、安定性の増加、水溶性の増加、および/または製剤化の容易さをもたらす融合タンパク質の作製法を提供する。一実施形態において、本発明は、ムチンドメインポリペプチドに連結されていない治療活性タンパク質と比較して、生理学的条件下または治療上許容される製剤中で、得られた融合体の可溶性形態での高い濃度を達成することができるように選択されるムチンドメインポリペプチドに治療活性タンパク質を連結するステップを含む、治療活性タンパク質の水溶性を増加させる方法を含む。融合タンパク質に組み込まれた場合に、活性タンパク質の水溶性の増加を付与するムチンドメインポリペプチドの性質に寄与する要因には、高率のグリコシル化、グリカンの種類、およびムチンドメインポリペプチドのアミノ酸の電荷が含まれる。いくつかの実施形態において、本方法は、生理学的条件下で、または治療上許容される製剤中で、ネイティブな治療活性タンパク質と比較して、水溶性が、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約90%、少なくとも約100%、少なくとも約150%、少なくとも約200%、少なくとも約400%、少なくとも約600%、少なくとも約800%、少なくとも約1000%、少なくとも約2000%、少なくとも約4000%、または少なくとも約6000%高い融合タンパク質をもたらす。 In another aspect, the present invention improves ease of manufacture associated with half-life extension techniques that require post-expression chemical coupling, and provides increased stability compared to native therapeutically active proteins, Methods of making fusion proteins that provide increased water solubility and / or ease of formulation are provided. In one embodiment, the invention provides a soluble form of the resulting fusion in physiological conditions or in a therapeutically acceptable formulation as compared to a therapeutically active protein that is not linked to a mucin domain polypeptide. A method of increasing the water solubility of a therapeutically active protein comprising linking the therapeutically active protein to a mucin domain polypeptide that is selected so that high concentrations can be achieved. Factors that contribute to the properties of mucin domain polypeptides that confer increased water solubility of the active protein when incorporated into fusion proteins include high rates of glycosylation, glycan types, and amino acids of mucin domain polypeptides. Charge is included. In some embodiments, the method has a water solubility of at least about 50%, at least about 60% compared to the native therapeutically active protein under physiological conditions or in a therapeutically acceptable formulation. At least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 400%, at least about 600%, at least about 800%, at least about 1000% Resulting in fusion proteins that are at least about 2000%, at least about 4000%, or at least about 6000% higher.
核酸配列
本発明は、本発明の融合タンパク質をコードする単離されたポリ核酸、および本発明の融合タンパク質をコードするポリ核酸分子に相補的な配列を提供する。別の態様において、本発明は、相同変異体を含む本発明の融合タンパク質をコードするポリ核酸および本発明の融合タンパク質に相補的な配列を生成する方法を包含する。一般的に、本発明は、融合タンパク質をコードするポリヌクレオチド配列を生成し、得られた遺伝子産物を発現する方法であって、ムチンドメインポリペプチドおよび活性タンパク質のそれぞれをコードするヌクレオチドを構築することと、構成要素をインフレームで連結することと、適切な発現ベクターにコード遺伝子を組み込むことと、発現ベクターで適切な宿主細胞を形質転換することと、融合タンパク質を形質転換された宿主細胞内で発現させることと、それによって本発明の融合タンパク質を産生することと、を含む方法を提供する。分子生物学における標準的な組換え技術を用いて、本発明のポリヌクレオチドおよび発現ベクターを作製することができる。本発明によれば、融合タンパク質をコードする核酸配列を用いて、適切な宿主細胞における融合タンパク質の発現を指向する組換えDNA分子を作製してもよい。いくつかのクローニング戦略は、本発明を実施するのに適していることが想定され、これらの多くを用いて、融合タンパク質またはその相補体をコードする遺伝子を含むコンストラクトを作製することができる。一実施形態において、クローニング方法を用いて、活性タンパク質およびムチンドメインポリペプチドを含む単量体融合タンパク質をコードする遺伝子を作製する。この段落で説明される上述の実施形態において、この遺伝子はさらに、切断配列(複数可)をコードすることもできるスペーサー配列をコードするヌクレオチドを含むことができる。
Nucleic Acid Sequences The present invention provides isolated polynucleic acids that encode the fusion proteins of the invention, and sequences that are complementary to polynucleic acid molecules that encode the fusion proteins of the invention. In another aspect, the invention includes a polynucleic acid encoding a fusion protein of the invention comprising a homologous variant and a method of generating a sequence complementary to the fusion protein of the invention. In general, the present invention is a method of generating a polynucleotide sequence encoding a fusion protein and expressing the resulting gene product comprising constructing nucleotides encoding each of a mucin domain polypeptide and an active protein. Linking the components in-frame, incorporating the coding gene into an appropriate expression vector, transforming an appropriate host cell with the expression vector, and within the host cell transformed with the fusion protein A method is provided that comprises expressing and thereby producing a fusion protein of the invention. Standard recombinant techniques in molecular biology can be used to make the polynucleotides and expression vectors of the invention. In accordance with the present invention, a nucleic acid sequence encoding a fusion protein may be used to make a recombinant DNA molecule that directs the expression of the fusion protein in a suitable host cell. Several cloning strategies are envisioned to be suitable for practicing the present invention, and many of these can be used to create a construct that includes a gene that encodes a fusion protein or its complement. In one embodiment, a cloning method is used to generate a gene that encodes a monomeric fusion protein comprising an active protein and a mucin domain polypeptide. In the above-described embodiments described in this paragraph, the gene can further include a nucleotide encoding a spacer sequence that can also encode the cleavage sequence (s).
一つのアプローチでは、最初に、融合タンパク質に対応するDNA配列を含むコンストラクトが調製される。活性タンパク質および/またはムチンポリペプチドドメインをコードするDNAは、活性タンパク質のmRNAを保有し、それを検出可能なレベルで発現すると考えられる組織または単離された細胞から、標準的な方法を用いて調製されるcDNAライブラリーから取得してもよい。必要であれば、cDNAに逆転写されていない可能性のあるmRNAの前駆体およびプロセシング中間体を検出するために、コード配列は、上記のSambrookらに記載されるような従来のプライマー伸長手順を用いて取得することができる。したがって、DNAは、そのような供給源から調製されたcDNAライブラリーから都合よく取得することができる。コード遺伝子(複数可)は、ゲノムライブラリから取得されるか、または公的に利用可能なデータベース、特許、または参考文献から取得されるDNA配列を用いて、当技術分野で公知の標準的な合成手順(例えば、自動核酸合成)によって作製することもできる。このような手順は、当技術分野で公知であり、科学文献および特許文献に十分に記載されている。例えば、配列は、活性タンパク質または活性タンパク質の断片もしくは変異体、またはムチンドメインポリペプチドのアミノ酸配列を含むCASレジストリまたはGenBankデータベース内のエントリに対応する、ケミカルアブストラクトサービス(CAS)の登録番号(アメリカ化学会発行)および/もしくはncbi.nlm.nih.govのワールドワイドウェブ上で利用可能な米国立バイオテクノロジー情報センター(NCBI)のウェブページを通じて利用可能なGenBankアクセッション番号から取得することができる。 In one approach, a construct is first prepared that includes a DNA sequence corresponding to the fusion protein. The DNA encoding the active protein and / or mucin polypeptide domain contains mRNA of the active protein and is expressed using standard methods from tissues or isolated cells thought to express it at detectable levels. It may be obtained from a prepared cDNA library. If necessary, in order to detect mRNA precursors and processing intermediates that may not be reverse transcribed into cDNA, the coding sequence can be modified using conventional primer extension procedures such as those described in Sambrook et al. Can be obtained using. Thus, DNA can be conveniently obtained from a cDNA library prepared from such a source. The coding gene (s) can be obtained from standard libraries known in the art using DNA sequences obtained from genomic libraries or from publicly available databases, patents, or references. It can also be prepared by procedures (eg, automated nucleic acid synthesis). Such procedures are known in the art and are well described in the scientific and patent literature. For example, the sequence may be a chemical abstract service (CAS) registration number (American Chemistry) corresponding to an entry in the CAS registry or GenBank database that contains the amino acid sequence of an active protein or fragment or variant of an active protein or mucin domain polypeptide. And / or GenBank accession numbers available through the National Biotechnology Information Center (NCBI) web page available on the world wide web at ncbi.nlm.nih.gov.
その後、活性タンパク質をコードする遺伝子またはポリヌクレオチドは、例えば、生物系における高レベルのタンパク質発現のための適切な転写および翻訳配列の制御下にあるプラスミドまたは他のベクターであり得るコンストラクトにクローニングすることができる。後者のステップでは、例えば、ムチンドメインポリペプチドをコードする第2の遺伝子またはポリヌクレオチドは、活性タンパク質をコードする遺伝子(複数可)と隣接し、インフレームでコンストラクトにクローニングすることによって、活性タンパク質遺伝子のN末端および/またはC末端をコードするヌクレオチドに遺伝的に融合される。 The gene or polynucleotide encoding the active protein is then cloned into a construct that can be, for example, a plasmid or other vector under the control of appropriate transcriptional and translational sequences for high level protein expression in biological systems. Can do. In the latter step, for example, the second gene or polynucleotide encoding a mucin domain polypeptide is adjacent to the gene (s) encoding the active protein and cloned into the construct in frame, thereby creating an active protein gene. Genetically fused to the N-terminal and / or C-terminal encoding nucleotides.
その後、融合ポリペプチドをコードする、得られたポリヌクレオチドは、個別に発現ベクターにクローニングすることができる。核酸配列は、多様な方法によってベクターに挿入することができる。一般に、DNAは、当該分野で公知の技術を用いて適切な制限エンドヌクレアーゼ部位(複数可)に挿入される。ベクター成分は、一般的に、シグナル配列、複製起点、1以上のマーカー遺伝子、エンハンサーエレメント、プロモーター、および転写終結配列のうちの1以上を含むが、これらに限定されない。これらの成分のうちの1以上を含む適切なベクターの構築は、当業者に公知の標準的なライゲーション技術を用いる。このような技術は当技術分野で公知であり、科学文献および特許文献で十分に説明されている。 The resulting polynucleotides encoding the fusion polypeptide can then be individually cloned into an expression vector. The nucleic acid sequence can be inserted into the vector by a variety of methods. In general, DNA is inserted into the appropriate restriction endonuclease site (s) using techniques known in the art. Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Construction of a suitable vector containing one or more of these components uses standard ligation techniques known to those skilled in the art. Such techniques are well known in the art and are well described in the scientific and patent literature.
適切なベクター、宿主、および発現系は、組換え発現の当業者に公知である。様々なベクターが公的に入手可能である。ベクターは、例えば、プラスミド、コスミド、ウイルス粒子、またはファージの形態であってもよい。両方の発現ベクターおよびクローニングベクターは、1以上の選択された宿主細胞においてベクターの複製を可能にする核酸配列を含み、さらに宿主細胞内での組換えタンパク質の発現および翻訳後修飾を可能にする。 Appropriate vectors, hosts, and expression systems are known to those skilled in the art of recombinant expression. Various vectors are publicly available. The vector may be, for example, in the form of a plasmid, cosmid, viral particle, or phage. Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells, and further allow for expression and post-translational modifications of the recombinant protein in the host cell.
本発明はまた、本明細書に開示される単量体融合タンパク質組成物を発現するための宿主細胞も提供する。適切な真核宿主細胞の例としては、サッカロミセス・セレビシエ、ピキア・パストリス、およびハンゼヌラ・ポリモルファなどの酵母宿主、ヨトウガSf9細胞、スポドプテラ・フルギペルダSf21、およびハイファイブ(High Five)細胞などの昆虫宿主、マウス線維芽細胞(C127−BPV)、チャイニーズハムスター卵巣細胞(CHO−DHFR、CHO−NEOSPLA、CHO−GS)、およびマウス骨髄腫細胞(NSO−GS)などの哺乳類宿主が挙げられるが、これらに限定されない。 The present invention also provides host cells for expressing the monomeric fusion protein compositions disclosed herein. Examples of suitable eukaryotic host cells include yeast hosts such as Saccharomyces cerevisiae, Pichia pastoris, and Hansenula polymorpha, insect hosts such as Spodoptera Sf9 cells, Spodoptera frugiperda Sf21, and High Five cells, Mammalian hosts such as, but not limited to, mouse fibroblasts (C127-BPV), Chinese hamster ovary cells (CHO-DHFR, CHO-NEOSPLA, CHO-GS), and mouse myeloma cells (NSO-GS). Not.
発現させた融合タンパク質は、当技術分野で公知の方法によって、または本明細書に開示される方法によって精製することができる。ゲル濾過、アフィニティー精製、塩分画、イオン交換クロマトグラフィー、サイズ排除クロマトグラフィー、ヒドロキシアパタイト吸着クロマトグラフィー、疎水性相互作用クロマトグラフィーおよびゲル電気泳動などの手順を使用してもよく、それぞれの手順は、それぞれの宿主細胞によって産生された融合タンパク質を回収し、精製するために調整されている。精製の方法は、Robert K.Scopes,Protein Purification:Principles and Practice(タンパク質の精製:原理と実践),Charles R.Castor(編集),Springer−Verlag 1994、および上記のSambrookらで説明されている。多段階の精製分離は、BaronらのCrit.Rev.Biotechnol.10:179−90(1990)およびBelowらのJ.Chromatogr.A.679:67−83(1994)にも記載されている。 The expressed fusion protein can be purified by methods known in the art or by the methods disclosed herein. Procedures such as gel filtration, affinity purification, salt fractionation, ion exchange chromatography, size exclusion chromatography, hydroxyapatite adsorption chromatography, hydrophobic interaction chromatography and gel electrophoresis may be used, It is tailored to recover and purify the fusion protein produced by each host cell. Methods of purification are described in Robert K. Scopes, Protein Purification: Principles and Practices (Protein Purification: Principles and Practices), Charles R. Castor (Editor), Springer-Verlag 1994, and Sambrook et al., Supra. Multi-step purification separations are also described in Baron et al., Crit. Rev. Biotechnol. 10: 179-90 (1990) and Below et al., J. Chromatogr.
医薬組成物
本発明は、本発明の融合タンパク質を含む医薬組成物を提供する。一実施形態において、医薬組成物、融合タンパク質および少なくとも1種類の薬学的に許容される担体を含む。本発明の融合タンパク質は、ポリペプチドが水溶液または緩衝液などの薬学的に許容される担体ビヒクル、薬学的に許容される懸濁剤および乳剤と組み合わされる薬学的に有用な組成物を調製するための公知の方法に従って製剤化することができる。非水性溶媒の例としては、プロピルエチレングリコール、ポリエチレングリコールおよび植物油が挙げられる。治療用製剤は、レミントンの薬学、第16版、Osol,A.編(1980)に記載されるように、凍結乾燥製剤または水溶液の形態で、任意の生理学的に許容される担体、賦形剤または安定剤と、所望の純度を有する活性成分とを混合することによって貯蔵のために調製される。
Pharmaceutical Composition The present invention provides a pharmaceutical composition comprising the fusion protein of the present invention. In one embodiment, comprises a pharmaceutical composition, a fusion protein and at least one pharmaceutically acceptable carrier. The fusion proteins of the invention are used to prepare pharmaceutically useful compositions in which the polypeptide is combined with a pharmaceutically acceptable carrier vehicle such as an aqueous solution or buffer, pharmaceutically acceptable suspensions and emulsions. It can be formulated according to known methods. Examples of non-aqueous solvents are propylethylene glycol, polyethylene glycol and vegetable oil. The therapeutic formulation can be any physiologically acceptable carrier, excipient in the form of a lyophilized formulation or an aqueous solution, as described in Remington's Pharmacy, 16th edition, Osol, A. Ed. (1980). Or it is prepared for storage by mixing the stabilizer and the active ingredient having the desired purity.
医薬組成物は、経口、鼻腔内、非経口または吸入療法により投与することができ、錠剤、トローチ剤、顆粒剤、カプセル剤、丸剤、アンプル剤、坐剤またはエアロゾルの形態を取ってもよい。医薬組成物はまた、水性もしくは非水性の希釈剤、シロップ剤、顆粒剤または散剤中の有効成分の懸濁液、溶液およびエマルジョンの形態をとってもよい。さらに、医薬組成物はまた、他の薬学的活性化合物または複数の本発明の化合物も含むことができる。 The pharmaceutical composition can be administered orally, intranasally, parenterally or by inhalation therapy and may take the form of tablets, troches, granules, capsules, pills, ampoules, suppositories or aerosols. . The pharmaceutical compositions may also take the form of suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granules or powders. In addition, the pharmaceutical composition can also contain other pharmaceutically active compounds or compounds of the invention.
さらに具体的には、本医薬組成物は、経口、直腸、経鼻、(経皮、エアロゾル、頬側および舌下を含む)局所、膣、(皮下、注入ポンプによる髄腔内、筋肉内、静脈内および皮内を含む)非経口、硝子体内、および肺を含む任意の適切な経路によって治療のために投与されてもよい。好ましい経路は、治療薬、レシピエントの病状および年齢、ならびに治療される疾患に応じて変化することも理解されるであろう。 More specifically, the pharmaceutical composition can be oral, rectal, nasal, topical (including transdermal, aerosol, buccal and sublingual), vaginal, (subcutaneous, intrathecal, intramuscular by infusion pump, It may be administered for treatment by any suitable route, including parenteral (including intravenous and intradermal), intravitreal, and lung. It will also be appreciated that the preferred route will vary depending on the therapeutic agent, the condition and age of the recipient, and the disease being treated.
好ましい実施形態において、組成物は、ヒトへの静脈内投与に適した医薬組成物としてルーチン手順に従って製剤化される。典型的には、静脈内投与用の組成物は、滅菌等張水性緩衝液中の溶液である。組成物が注入により投与される場合、無菌の医薬グレードの水または生理食塩水を含む注入ボトルに分注することができる。組成物が注射により投与される場合、成分が投与前に混合できるように、注射用滅菌水または生理食塩水のアンプルを提供することができる。 In a preferred embodiment, the composition is formulated according to routine procedures as a pharmaceutical composition suitable for intravenous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
別の好ましい実施形態において、医薬組成物は皮下に投与される。この実施形態において、本組成物は、投与前に再構成される凍結乾燥粉末として供給されてもよい。この組成物はまた、患者に直接投与することができる液体形態で供給されてもよい。一実施形態において、本組成物は、患者が容易に本組成物を自己投与することができるように、プレフィルドシリンジ中の液体として供給される。 In another preferred embodiment, the pharmaceutical composition is administered subcutaneously. In this embodiment, the composition may be supplied as a lyophilized powder that is reconstituted prior to administration. The composition may also be supplied in a liquid form that can be administered directly to the patient. In one embodiment, the composition is supplied as a liquid in a prefilled syringe so that the patient can easily self-administer the composition.
別の実施形態において、本発明の組成物は、長期間にわたって制御された様式で有益な活性薬剤を送達することに有用性を示しているリポソームにカプセル化される。リポソームは、封入された水性容量を含む二重膜で閉じられている。リポソームはまた、単一の膜二重層を有する単層小胞または複数の膜二重層を有する多層小胞であってもよく、それぞれ水層によって隣のものから分離される。結果として生じる膜二重層の構造は、脂質の疎水性(非極性)尾部が二重層の中心に向かって方向付けられるが、親水性(極性)頭部は水相に向かって方向付けられるようになっている。一実施形態において、リポソームは、単核食細胞系の臓器、主に肝臓および脾臓による取り込みを回避する柔軟な水溶性ポリマーでコーティングすることができる。リポソームを囲むのに適した親水性ポリマーには、米国特許第6,316,024号、同第6、126,966号、同第6,056,973号および同第6,043,094号(これらの内容は、参照によりその全体が援用される)に記載のPEG、ポリビニルピロリドン、ポリビニルメチルエーテル、ポリメチルオキサゾリン、ポリエチルオキサゾリン、ポリヒドロキシプロピルオキサゾリン、ポリヒドロキシプロピルメタクリルアミド、ポリメタクリルアミド、ポリジメチルアクリルアミド、ポリヒドロキシプロピルメタクリレート、ポリヒドロキシエチルアクリレート、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ポリエチレングリコール、ポリアスパルタミドおよび親水性ペプチド配列が含まれるが、これらに限定されない。 In another embodiment, the compositions of the invention are encapsulated in liposomes that have shown utility in delivering beneficial active agents in a controlled manner over an extended period of time. Liposomes are closed with a bilayer containing an encapsulated aqueous volume. Liposomes can also be unilamellar vesicles with a single membrane bilayer or multilamellar vesicles with multiple membrane bilayers, each separated from the next by an aqueous layer. The resulting membrane bilayer structure is such that the hydrophobic (nonpolar) tail of the lipid is directed towards the center of the bilayer, while the hydrophilic (polar) head is oriented towards the aqueous phase. It has become. In one embodiment, the liposomes can be coated with a flexible water soluble polymer that avoids uptake by organs of the mononuclear phagocyte system, primarily the liver and spleen. Hydrophilic polymers suitable for surrounding liposomes include US Pat. Nos. 6,316,024, 6,126,966, 6,056,973, and 6,043,094 ( These contents are incorporated by reference in their entirety), PEG, polyvinyl pyrrolidone, polyvinyl methyl ether, polymethyl oxazoline, polyethyl oxazoline, polyhydroxypropyl oxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, poly Includes but is not limited to dimethylacrylamide, polyhydroxypropyl methacrylate, polyhydroxyethyl acrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethylene glycol, polyaspartamide and hydrophilic peptide sequences It is not.
リポソームは、当技術分野で公知の任意の脂質または脂質の組み合せで構成されてもよい。例えば、小胞形成脂質は、米国特許第6,056,973号および同第5,874、104号に開示されるようなホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジン酸、ホスファチジルセリン、ホスファチジルグリセロール、ホスファチジルイノシトール、およびスフィンゴミエリンなどのリン脂質を含む天然脂質または合成脂質であってもよい。小胞を形成する脂質はまた、米国特許第6,056,973号にも開示されている1,2−ジオレイルオキシ−3−(トリメチルアミノ)プロパン(DOTAP);N−[1−(2,3−ジテトラデシルオキシ)プロピル]−N,N−ジメチル−N−ヒドロキシエチルアンモニウムブロミド(DMRIE);N−[1−(2,3−ジオレイルオキシ)プロピル]−N,N−ジメチル−N−ヒドロキシエチルアンモニウムブロミド(DORIE);N−[1−(2,3−ジオレイルオキシ)プロピル]−N,N,N−トリメチルアンモニウムクロリド(DOTMA);3[Ν−(Ν’,Ν'−ジメチルアミノエタン)カルバモイル]コレステロール(DC−Chol);またはジメチルジオクタデシルアンモニウム(DDAB)などの糖脂質、セレブロシド、またはカチオン性脂質であってもよい。コレステロールも、米国特許第5,916,588号および同第5,874,104号に開示されているような小胞に安定性を付与するために適切な範囲で存在してもよい。 Liposomes may be composed of any lipid or combination of lipids known in the art. For example, vesicle-forming lipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, as disclosed in US Pat. Nos. 6,056,973 and 5,874,104, And natural or synthetic lipids including phospholipids such as sphingomyelin. Lipids that form vesicles are also disclosed in US Pat. No. 6,056,973, 1,2-dioleoyloxy-3- (trimethylamino) propane (DOTAP); N- [1- (2 , 3-Ditetradecyloxy) propyl] -N, N-dimethyl-N-hydroxyethylammonium bromide (DMRIE); N- [1- (2,3-dioleyloxy) propyl] -N, N-dimethyl- N-hydroxyethylammonium bromide (DORIE); N- [1- (2,3-dioleyloxy) propyl] -N, N, N-trimethylammonium chloride (DOTMA); 3 [Ν- (Ν ', Ν' -Dimethylaminoethane) carbamoyl] cholesterol (DC-Chol); or glycolipids such as dimethyldioctadecylammonium (DDAB), cerebroside Or it may be cationic lipids. Cholesterol may also be present in a suitable range to impart stability to the vesicles as disclosed in US Pat. Nos. 5,916,588 and 5,874,104.
液体製剤については、所望の特性は、製剤が、静脈内、筋肉内、関節内、または皮下投与のための25、28、30、31、32ゲージ針を通過することができる形態で供給されることである。 For liquid formulations, the desired properties are provided in a form that allows the formulation to pass through a 25, 28, 30, 31, 32 gauge needle for intravenous, intramuscular, intraarticular, or subcutaneous administration. That is.
他の実施形態において、組成物は、CNSへの嗅覚路を通る活性薬剤の移動を可能にし、全身投与を減少させるために鼻腔内、頬側、または舌下経路を介して脳へ送達されてもよい。この投与経路のために一般的に使用される装置は、米国特許第6,715,485号に含まれる。この経路を介して送達される組成物は、CNS投与を増加させるか、または特定の薬物に関連した全身毒性リスクを低減する総身体負荷を軽減し得る。皮下埋め込み型デバイスにおける送達のための医薬組成物の調製は、例えば、米国特許第3,992,518号、同第5,660,848号、および同第5,756,115号に記載されるものなどの当技術分野で公知の方法を用いて行うことができる。 In other embodiments, the composition is delivered to the brain via the intranasal, buccal, or sublingual route to allow migration of the active agent through the olfactory tract to the CNS and reduce systemic administration. Also good. Devices commonly used for this route of administration are included in US Pat. No. 6,715,485. Compositions delivered via this route may reduce total body burden that increases CNS administration or reduces systemic toxicity risks associated with certain drugs. The preparation of pharmaceutical compositions for delivery in subcutaneous implantable devices is described, for example, in US Pat. Nos. 3,992,518, 5,660,848, and 5,756,115. Can be performed using methods known in the art such as
実施例
以下の実施例は、例示のために提供され、決して特許請求の範囲のように本発明を限定するものとして解釈されるべきではない。
EXAMPLES The following examples are provided for purposes of illustration, and are not to be construed as limiting the invention in any way as claimed.
実施例1.ムチンドメイン融合コンストラクトの設計、調製、発現、および精製
1.ムチン化IL−1Ra融合タンパク質の設計
様々な長さのムチン化を有するIL−1Raの融合タンパク質を設計した。ムチンドメインの長さは、ムチンタンデムリピートの数を変化させることによって系統的に増加させた。融合タンパク質のムチン化ドメインは、ヒトMUC20タンパク質由来のタンデムリピート(TR)に基づいていた。IL−1Raと2TR、4TR、6TR、8TR、および12TRの融合タンパク質を設計し、それぞれRDB1813[配列番号1(タンパク質);配列番号2(DNA)]、RDB1814[配列番号3(タンパク質);配列番号4(DNA)]、RDB1826[配列番号5(タンパク質);配列番号6(DNA)]、RDB1815[配列番号7(タンパク質);配列番号8(DNA)]、ならびにRDB1816[配列番号9(タンパク質);配列番号10(DNA)]と命名した。4グリシン(GGGG(配列番号:27))のリンカーを、IL−1Ra配列のC末端と第1のムチンTRとの間、および2つのムチンTRの各セットの間に挿入した。精製を容易にするためにHisタグをRDB1813、RDB1814、RDB1815、およびRDB1816のC末端に付加し、FLAGタグをRDB1826のC末端に付加した。
Example 1. Design, preparation, expression and purification of mucin domain fusion constructs Design of mucinized IL-1Ra fusion proteins IL-1Ra fusion proteins with various lengths of mucinization were designed. The length of the mucin domain was systematically increased by changing the number of mucin tandem repeats. The mucinization domain of the fusion protein was based on tandem repeats (TR) from human MUC20 protein. IL-1Ra and 2TR, 4TR, 6TR, 8TR, and 12TR fusion proteins were designed and RDB1813 [SEQ ID NO: 1 (protein); SEQ ID NO: 2 (DNA)], RDB1814 [SEQ ID NO: 3 (protein); SEQ ID NO: 4 (DNA)], RDB1826 [SEQ ID NO: 5 (protein); SEQ ID NO: 6 (DNA)], RDB1815 [SEQ ID NO: 7 (protein); SEQ ID NO: 8 (DNA)], and RDB1816 [SEQ ID NO: 9 (protein); SEQ ID NO: 10 (DNA)]. A linker of 4 glycine (GGGG (SEQ ID NO: 27)) was inserted between the C-terminus of the IL-1Ra sequence and the first mucin TR and between each set of two mucin TRs. A His tag was added to the C-terminus of RDB1813, RDB1814, RDB1815, and RDB1816, and a FLAG tag was added to the C-terminus of RDB1826 to facilitate purification.
2.ムチン化エキセンジン−4融合タンパク質RDB2203の設計
ヒトMUC20タンパク質からの8TRとエキセンジン−4の融合タンパク質を設計した:RDB2203[配列番号24]。4グリシン(GGGG(配列番号:27))のリンカーを、エキセンジン−4配列のC末端と第1のムチンTRとの間、および2つのムチンTRの各セットの間に挿入した。精製を容易にするためにHisタグをC末端に付加し、スペーサー(GGGGS(配列番号28)を最後のTRとHIS−タグとの間に挿入した。
2. Design of mucinized exendin-4 fusion protein RDB2203 An 8TR and exendin-4 fusion protein from human MUC20 protein was designed: RDB2203 [SEQ ID NO: 24]. A linker of 4 glycine (GGGG (SEQ ID NO: 27)) was inserted between the C-terminus of the exendin-4 sequence and the first mucin TR and between each set of two mucin TRs. A His tag was added to the C-terminus to facilitate purification and a spacer (GGGGGS (SEQ ID NO: 28)) was inserted between the last TR and the HIS-tag.
3.遺伝子合成
設計したコンストラクトの発現のための遺伝子合成を、標準的な方法を用いて行った。
3. Gene synthesis Gene synthesis for the expression of the designed constructs was performed using standard methods.
4.哺乳類発現ベクターへの合成遺伝子のサブクローニング
A)発現ベクターpcDNA(商標)(Invitrogen社)の調製
pcDNA5μgを、37℃で2時間、BamHIおよびHindIIIで消化した。この消化物を、5’リン酸を除去するために仔ウシアルカリホスファターゼで処理し、したがって、ベクターそれ自体の再連結を防止した。緩衝液を交換し、仔ウシアルカリホスファターゼ反応から塩を除去した。メーカーの推奨プロトコルに従って、Qiagen社のPCRのクリーンアップキットを使用した。DNAを、H2030μlで溶出した。
4). Subcloning of synthetic genes into mammalian expression vectors A) Preparation of expression vector pcDNA ™ (Invitrogen) 5 μg of pcDNA was digested with BamHI and HindIII at 37 ° C. for 2 hours. This digest was treated with calf alkaline phosphatase to remove 5 'phosphate, thus preventing religation of the vector itself. The buffer was changed to remove salts from the calf alkaline phosphatase reaction. A Qiagen PCR cleanup kit was used according to the manufacturer's recommended protocol. DNA was eluted with 30 μl H20.
B)目的の遺伝子の調製
目的の遺伝子を、37℃で2時間、BamHIおよびHindIIIで消化した。消化反応を、0.8%SYBRグリーンを用いるE−Gel(登録商標)クローンウェル(商標)装置(Invitrogen社)で行った。目的の遺伝子に対応する断片をゲルのウェルの第2列から単離した。
B) Preparation of gene of interest The gene of interest was digested with BamHI and HindIII for 2 hours at 37 ° C. The digestion reaction was performed on an E-Gel® Clone Well ™ device (Invitrogen) using 0.8% SYBR green. The fragment corresponding to the gene of interest was isolated from the second row of gel wells.
C)pcDNAへの遺伝子のライゲーション反応
調製したpcDNA(ステップA)を、T4リガーゼの存在下で、ステップBのDNAと混合し、30分間室温でインキュベートした。ライゲーション後、生成物をTOP10細胞(Invitrogen社;大腸菌の化学的コンピテント菌株)に形質転換し、正しいクローンを採取し、−80℃でグリセロールストックとして保存した。
C) Gene Ligation Reaction to pcDNA The prepared pcDNA (Step A) was mixed with Step B DNA in the presence of T4 ligase and incubated at room temperature for 30 minutes. After ligation, the product was transformed into TOP10 cells (Invitrogen; chemically competent E. coli strain) and the correct clones were picked and stored as glycerol stocks at -80 ° C.
5.ムチン化IL−1Raおよびエキセンジン−4融合タンパク質の発現
全てのタンパク質を、製造業者のプロトコルに従ってFreeStyle(商標)MAX試薬(Invitrogen社)を用いてCHO細胞中で発現させた。簡単に述べると、トランスフェクションの前日に、細胞を0.5×106細胞/mLで播種し、トランスフェクションの日に、製造業者が推奨するとおりに細胞を1×106細胞/mLに調整した。1リットルのトランスフェクションについては、培地(OptiPRO(商標)、Invitrogen社)の2本のチューブ(AおよびB)を調製し、それぞれ約19mL含んでいた。DNA1mgをチューブAに添加し、FreeStyle(商標)MAX試薬1mlをチューブBに添加した。両方のチューブの内容物を直ちに混合し、15分間室温でインキュベートした。インキュベーション期間後に、混合物をCHO細胞1リットルにゆっくりと添加した。トランスフェクション後、これらの細胞を6〜7日間放置し、次いで上清を回収した。
5. Expression of mucinated IL-1Ra and exendin-4 fusion proteins All proteins were expressed in CHO cells using FreeStyle ™ MAX reagent (Invitrogen) according to the manufacturer's protocol. Briefly, the day before transfection, cells were seeded at 0.5 × 10 6 cells / mL, and on the day of transfection, cells were adjusted to 1 × 10 6 cells / mL as recommended by the manufacturer. did. For 1 liter transfection, two tubes (A and B) of media (OptiPRO ™, Invitrogen) were prepared, each containing approximately 19 mL. 1 mg of DNA was added to tube A and 1 ml of FreeStyle ™ MAX reagent was added to tube B. The contents of both tubes were mixed immediately and incubated for 15 minutes at room temperature. After the incubation period, the mixture was slowly added to 1 liter of CHO cells. After transfection, these cells were left for 6-7 days and then the supernatant was collected.
6.ムチン化IL−1Raおよびエキセンジン−4融合タンパク質の精製
Hisタグ発現タンパク質の精製をニッケルカラム上で行った。タンパク質結合後、カラムを最大5カラム容積の緩衝液A(50mMのトリスpH8および500mMのNaCl)で洗浄した。結合タンパク質を、イミダゾールの濃度を増加させて(20〜500mM)溶出した。精製タンパク質をPBSに対して一晩透析した。
6). Purification of mucinized IL-1Ra and exendin-4 fusion protein Purification of His-tagged protein was performed on a nickel column. After protein binding, the column was washed with up to 5 column volumes of buffer A (50
RDB1826を抗FLAGカラムで精製した。タンパク質結合後、カラムを最大5カラム容積のPBSで洗浄した。タンパク質をpH3で溶出し、トリス緩衝液pH7で直接中和した。精製タンパク質をPBSに対して一晩透析した。
RDB1826 was purified on an anti-FLAG column. After protein binding, the column was washed with up to 5 column volumes of PBS. The protein was eluted at
実施例2.ムチン化IL−1Raコンストラクトの分子量およびpI
IL−1Raムチン融合タンパク質RDB1813(IL1Ra2TR)、RDB1814(IL1Ra4TR)、RDB1815(IL1Ra8TR)、およびRDB1816(IL1Ra12TR)をSDS/PAGEを用いて特徴づけた(図1A)。全てのコンストラクトの見かけの分子量は、ポリペプチド配列の計算された分子量よりも著しく高く、予想される高レベルのグリコシル化と一致した。RDB1813、RDB1814、RDB1815、およびRDB1816のポリペプチドのそれぞれ計算された分子量は、22kD、26.2kD、34.8kDおよび43.3kDであり、ゲル上でのそれらの移動に基づくそれぞれの見かけの分子量は35kD、45kD、65kDおよび80kDである(図1A;下)。
Example 2 Molecular weight and pI of mucinized IL-1Ra construct
The IL-1Ra mucin fusion proteins RDB1813 (IL1Ra2TR), RDB1814 (IL1Ra4TR), RDB1815 (IL1Ra8TR), and RDB1816 (IL1Ra12TR) were characterized using SDS / PAGE (FIG. 1A). The apparent molecular weight of all constructs was significantly higher than the calculated molecular weight of the polypeptide sequence, consistent with the expected high level of glycosylation. The calculated molecular weights of the RDB1813, RDB1814, RDB1815, and RDB1816 polypeptides are 22 kD, 26.2 kD, 34.8 kD, and 43.3 kD, respectively, and the apparent molecular weight based on their migration on the gel is 35 kD, 45 kD, 65 kD and 80 kD (FIG. 1A; bottom).
コンストラクトRDB1813(IL1Ra2TR)、RDB1826(IL1Ra6TR)、RDB1815(IL1Ra8TR)、およびRDB1816(IL1Ra12TR)の等電点を、等電点電気泳動を用いて測定した(図1B)。全てのコンストラクトは、電荷に関して不均一であり、タンパク質のPIの周辺に複数のバンドがあった。タンパク質のPIは、大部分がポリペプチド配列に基づくそれらの計算されたPIと一致し、O−グリカンは高度にシアル化されていないことが示唆された。バンドの多重度は、Nグリコシル化の違いによる可能性が最も高い。 The isoelectric points of the constructs RDB1813 (IL1Ra2TR), RDB1826 (IL1Ra6TR), RDB1815 (IL1Ra8TR), and RDB1816 (IL1Ra12TR) were measured using isoelectric focusing (FIG. 1B). All constructs were heterogeneous with respect to charge, with multiple bands around the protein PI. Protein PIs were largely consistent with their calculated PIs based on polypeptide sequences, suggesting that O-glycans are not highly sialylated. Band multiplicity is most likely due to differences in N-glycosylation.
全てのコンストラクトを、スーパーデックス200カラム(図2〜6)上での分析用ゲル濾過によってさらに特徴付けた。ゲルろ過は、未変性条件下でのそれらの流体力学容積に基づいてタンパク質を分離する(すなわち、SDS/PAGEとは異なり、非変性である)。溶出時間は、未知の球状タンパク質の見かけの分子量を算出することができるような球状タンパク質標準物質を用いて較正することができる。溶出時間は、実際の分子量よりも流体力学半径に直接関係しており、それらの計算された分子量よりも有意に高い見かけの分子量が、非球状(すなわち、細長いまたはロッド状)構造、高レベルのグリコシル化、および/または高レベルの水和を示唆する。
All constructs were further characterized by analytical gel filtration on a
ゲルろ過では、RDB1813、RDB1814、RDB1826、RDB1815、およびRDB1816の見かけの分子量は、それぞれ42kD、50kD、118kD、139kD、および230kDである(図2〜6)。全てのムチンコンストラクトの見かけの分子量は、(アミノ酸配列のみに基づく)それらの計算された分子量およびSDS/PAGE上での移動度の両方よりも著しく高かった。これらの観察は、高レベルのグリコシル化およびムチンコンストラクトの予想される棒状構造の両方と高度に一致する。 In gel filtration, the apparent molecular weights of RDB1813, RDB1814, RDB1826, RDB1815, and RDB1816 are 42 kD, 50 kD, 118 kD, 139 kD, and 230 kD, respectively (FIGS. 2-6). The apparent molecular weight of all mucin constructs was significantly higher than both their calculated molecular weight (based only on amino acid sequence) and mobility on SDS / PAGE. These observations are highly consistent with both high levels of glycosylation and the expected rod-like structure of the mucin construct.
実施例3.ムチンIL−1Raコンストラクトのアンタゴニスト活性
HEK−Blue(商標)IL−1β細胞(Invivogen社)は、NF−κB/AP−1分泌型胚性アルカリホスファターゼ(SEAP)レポーター遺伝子のIL−1β誘導発現を監視することによって、生物活性のあるIL−1βをインビトロで検出するように特別に設計されたヒト胚性腎臓細胞である。SEAPは、SEAP検出試薬のQUANTI−Blue(商標)(Invivogen社)を使用した場合に容易に監視することができる。IL−1Raは、IL−1RIとの結合を介してIL−1β誘導シグナルを阻害し、IL−1RAcPの結合を阻止し、したがって完全なシグナル伝達複合体のアセンブリを阻止する。ムチンIL1RaコンストラクトのRDB1813(IL1Ra2TR)、RDB1814(IL1Ra4TR)、RDB1826(IL1Ra6TR)、RDB1815(IL1Ra8TR)、およびRDB1816(IL1Ra12TR)のIL−1β誘発性SEAPを阻害する能力を評価した。融合されたムチンドメインを欠くIL1Ra(アナキンラ)を陽性のアンタゴニスト対照として使用した。
Example 3 Antagonist activity of mucin IL-1Ra construct HEK-Blue ™ IL-1β cells (Invivogen) monitor IL-1β-induced expression of NF-κB / AP-1 secreted embryonic alkaline phosphatase (SEAP) reporter gene To human embryonic kidney cells specifically designed to detect bioactive IL-1β in vitro. SEAP can be easily monitored when using the SEAP detection reagent QUANTI-Blue ™ (Invivogen). IL-1Ra inhibits IL-1β-induced signals through binding to IL-1RI and blocks IL-1RAcP binding, thus preventing assembly of the complete signaling complex. The ability of mucin IL1Ra constructs to inhibit IL-1β-induced SEAP of RDB1813 (IL1Ra2TR), RDB1814 (IL1Ra4TR), RDB1826 (IL1Ra6TR), RDB1815 (IL1Ra8TR), and RDB1816 (IL1Ra12TR) was evaluated. IL1Ra lacking a fused mucin domain (anakinra) was used as a positive antagonist control.
HEK−Blue(商標)IL−1β細胞を含む培地100μLを、50,000細胞/ウェルの最終濃度になるように96ウェルマイクロタイタープレートに播種した。ムチンIL1RaコンストラクトRDB1813(IL1Ra2TR)、RDB1814(IL1Ra4TR)、RDB1826(IL1Ra6TR)、RDB1815(IL1Ra8TR)、およびRDB1816(IL1Ra12TR)を、12nM(RDB1813)、4.8nM(RDB1814)、34.5nM(RDB1826)、2.4nM(RDB1815)、および11.6nM(RDB1816)の初期濃度で調製し、その後、連続希釈して、2組ずつHEK−Blue(商標)IL−1β細胞に試験試料を添加した。SEAPを誘導するために、0.015nMのIL−1βを全ての試験試料中で使用した。0.117nMのIL−1βのみ、および11.76nMのIL1Ra+0.015nMのIL−1βを、陽性試料中で使用した。これらの試料を、37℃で20〜24時間インキュベートし、QUANTI−Blue(商標)アッセイを用いて評価した。 100 μL of medium containing HEK-Blue ™ IL-1β cells was seeded in a 96-well microtiter plate to a final concentration of 50,000 cells / well. Mucin IL1Ra constructs RDB1813 (IL1Ra2TR), RDB1814 (IL1Ra4TR), RDB1826 (IL1Ra6TR), RDB1815 (IL1Ra8TR), and RDB1816 (IL1Ra12TR), 12nM (RDB1813), 4.8nM (RDB1814), 34DB Test samples were added to HEK-Blue ™ IL-1β cells in duplicate, prepared at initial concentrations of .4 nM (RDB1815) and 11.6 nM (RDB1816), then serially diluted. To induce SEAP, 0.015 nM IL-1β was used in all test samples. Only 0.117 nM IL-1β and 11.76 nM IL1Ra + 0.015 nM IL-1β were used in the positive samples. These samples were incubated at 37 ° C. for 20-24 hours and evaluated using the QUANTI-Blue ™ assay.
ムチン−IL1RaコンストラクトのRDB1813(IL1Ra2TR)、RDB1814(IL1Ra4TR)、RDB1826(IL1Ra6TR)、RDB1815(IL1Ra8TR)、およびRDB1816(IL1Ra12TR)は、用量依存的にIL−1β誘発性SEAP発現を阻害し、0.1〜0.15nMの対照(未修飾IL1Ra)のIC50値と有利に比較すると、それぞれのIC50値は0.72nM、0.37nM、3.5nM、0.42nMの値、および0.53nMであった(図7〜9)。したがって、全てのムチン化コンストラクトの阻害活性は、未修飾IL1Ra(非ムチン化)タンパク質対照の数倍以内である。 Mucin-IL1Ra constructs RDB1813 (IL1Ra2TR), RDB1814 (IL1Ra4TR), RDB1826 (IL1Ra6TR), RDB1815 (IL1Ra8TR), and RDB1816 (IL1Ra12TR) inhibit IL-1β-induced SEAP expression in a dose-dependent manner. Compared advantageously with the IC 50 value of the control (unmodified IL1Ra) of ˜0.15 nM, the respective IC 50 values are 0.72 nM, 0.37 nM, 3.5 nM, 0.42 nM, and 0.53 nM. (FIGS. 7-9). Therefore, the inhibitory activity of all mucinized constructs is within several times that of the unmodified IL1Ra (non-mucinized) protein control.
実施例4.ムチンIL−1RaのIL−1RIへの結合親和性
IL−1RI_Fc(融合タンパク質)を、ヒト抗体捕捉キット(GEヘルスケア社)を用いてビアコア(商標)センサーチップ上に固定化した。未修飾IL−1Ra(陽性結合対照)、RDB1813(IL1Ra2TR)、RDB1814(IL1Ra4TR)、RDB1815(IL1Ra8TR)、RDB1816(IL1Ra12TR)、およびRDB1826(IL1Ra6TR)を5つの濃度:20nM、6.6nM、2.2nM、0.74nMおよび0.24nMでチップ上に流した。最初のサイクルでは、0.24nM濃度の特定のコンストラクトを、チップの表面に結合したリガンド上に180秒間流し、その後、分析物を解離させるためにブランク溶液を表面上に通過させた。同じ手順を、各コンストラクトについて0.74〜20nMの濃度の増加を使用して、さらに4回繰り返した。得られたセンサーグラムを、これらのコンストラクトの結合親和性を計算するために、ネイティブ機器ソフトウェアを用いて分析した(図10〜14)。
Example 4 The binding affinity IL-1RI_Fc (fusion protein) of mucin IL-1Ra to IL-1RI was immobilized on a Biacore ™ sensor chip using a human antibody capture kit (GE Healthcare). Unmodified IL-1Ra (positive binding control), RDB1813 (IL1Ra2TR), RDB1814 (IL1Ra4TR), RDB1815 (IL1Ra8TR), RDB1816 (IL1Ra12TR), and RDB1826 (IL1Ra6TR) in five concentrations: 20 nM, 6.6 nM, 2.2 nM , 0.74 nM and 0.24 nM. In the first cycle, a specific construct at a concentration of 0.24 nM was run over the ligand bound to the surface of the chip for 180 seconds, after which the blank solution was passed over the surface to dissociate the analyte. The same procedure was repeated four more times using increasing concentrations of 0.74-20 nM for each construct. The resulting sensorgrams were analyzed using native instrument software to calculate the binding affinity of these constructs (FIGS. 10-14).
細胞ベースアッセイからのそれらの活性データと一致して、全てのコンストラクトは、IL−1RIに対する強力な結合親和性を保持していた。RDB1813(IL1Ra2TR)、RDB1814(IL1Ra4TR)、RDB1826(IL1Ra6TR)、1815RDB(IL1Ra8TR)、およびRDB1816(IL1Ra12TR)についてのIL−1RIに対する計算された結合定数(KD)は、それぞれ240pM、64pM、526pM、160pM、および900pMであった。したがって、ムチン化コンストラクトの結合親和性は、KDが52pMであると決定された未修飾IL−1Raよりも4.6倍(RDB1813)、1.2倍(RDB1814)、10倍(1826RDB)、3.1倍(RDB1815)、および17.3倍(RDB1816)高い。IL−1RIに対して最も弱い親和性を有するコンストラクト(すなわち、RDB1816)は、連続するムチンタンデムリピートの最大数(12TR)を有していたことに留意することが重要である。したがって、RDB1816(Kd=1.4×10−4)の解離速度(Kd)が、未修飾IL−1Ra(Kd=1.5×10−4)と同じであるように、RDB1816の親和性の減少は、未修飾IL−1Ra(Ka=2.8×106)と比較した場合のより遅い会合速度(Ka=1.5×105)が主な原因であり、おそらくより遅いタンブリング速度が原因であった。 Consistent with their activity data from cell-based assays, all constructs retained strong binding affinity for IL-1RI. The calculated binding constants (K D ) for IL-1RI for RDB1813 (IL1Ra2TR), RDB1814 (IL1Ra4TR), RDB1826 (IL1Ra6TR), 1815RDB (IL1Ra8TR), and RDB1816 (IL1Ra12TR) are 240 pM, 64 pM, 526 pM, respectively. , And 900 pM. Therefore, binding affinities of mucin of constructs, 4.6 times than unmodified IL-1Ra to a K D was determined to be 52pM (RDB1813), 1.2 times (RDB1814), 10 times (1826RDB), 3.1 times higher (RDB1815) and 17.3 times higher (RDB1816). It is important to note that the construct with the weakest affinity for IL-1RI (ie, RDB1816) had the maximum number of consecutive mucin tandem repeats (12TR). Therefore, RDB1816 dissociation rate (K d = 1.4 × 10 -4 ) (K d) is, as the same as the unmodified IL-1Ra (K d = 1.5 × 10 -4), the RDB1816 The decrease in affinity is mainly due to the slower association rate (K a = 1.5 × 10 5 ) when compared to unmodified IL-1Ra (K a = 2.8 × 10 6 ), probably The slower tumbling speed was the cause.
実施例5.RDB1816のインビボ有効性
RDB1816(IL1Ra12TR)の作用の有効性および持続時間を、マウスコラーゲン抗体誘発性関節炎(CAIA)モデルで評価した。このモデルにおいて、未修飾IL−1Raは、6mg/kg/時間の速度で連続注入した場合に活性があるが、その非常に短い半減期により、20mg/kgの単回用量としては効果がない。
Example 5 FIG. In vivo efficacy of RDB1816 The efficacy and duration of action of RDB1816 (IL1Ra12TR) was evaluated in a mouse collagen antibody-induced arthritis (CAIA) model. In this model, unmodified IL-1Ra is active when continuously infused at a rate of 6 mg / kg / hour, but due to its very short half-life, it is not effective as a single dose of 20 mg / kg.
群当たり8匹のnでのマウスCAIAモデルの実験計画を図15に示す。簡単に説明すると、マウスにおける関節炎を、抗コラーゲン抗体カクテルの静脈内(IV)注射により開始する。3日後、炎症反応をリポ多糖(LPS)の腹腔内(IP)注射によりブーストし、同時に、試験化合物RDB1816(20mg/kg)およびアナキンラ(未修飾IL−1Ra、20mg/kg)、ならびに生理食塩水対照を皮下(SC)送達した。炎症の程度を評価するために、足の体積を複数の日にわたって測定した。 The experimental design of a mouse CAIA model with 8 n per group is shown in FIG. Briefly, arthritis in mice is initiated by intravenous (IV) injection of an anti-collagen antibody cocktail. After 3 days, the inflammatory response was boosted by intraperitoneal (IP) injection of lipopolysaccharide (LPS) and simultaneously tested compounds RDB1816 (20 mg / kg) and anakinra (unmodified IL-1Ra, 20 mg / kg), and saline Controls were delivered subcutaneously (SC). To assess the degree of inflammation, paw volume was measured over multiple days.
マウスCAIA実験の結果を図16に示す。アナキンラ処置群は、生理食塩水対照と比較して炎症の低下を示さなかった。これは、アナキンラの連続注入がこのモデルにおいて有効であるので、低暴露をもたらすその短い半減期に起因する。著しく対照的に、生理食塩水処置およびアナキンラ処理群の両方と比較して、足の体積の著しい減少がRDB1816処置マウスにおいて観察された。したがって、ムチン化が、IL−1Ra分子の暴露を著しく増加させ、薬力学的効果を引き出した。 The results of the mouse CAIA experiment are shown in FIG. The anakinra treated group showed no reduction in inflammation compared to the saline control. This is due to its short half-life resulting in low exposure since continuous infusion of anakinra is effective in this model. In marked contrast, a significant decrease in paw volume was observed in RDB1816 treated mice compared to both the saline treated and anakinra treated groups. Thus, mucinization significantly increased exposure of IL-1Ra molecules and elicited pharmacodynamic effects.
実施例6.RDB1815およびRDB1816の薬物動態(PK)
2種類のIL−1Raムチン融合ポリペプチドコンストラクト:RDB1815およびRDB1816の半減期を決定するために、ラットにおいて薬物動態学的研究を行った。用量群あたりn=3匹のラットで、RDB1815の単回用量を皮下(5.6mg/Kg)または静脈内(2.1mg/Kg)に送達し、RDB1816の単回用量を皮下(6.4mg/Kg)または静脈内(2.4mg/Kg)に送達した。血液を6日間にわたって様々な時点で採取し、ELISAによりIL−1Raについて分析した。
Example 6 Pharmacokinetics (PK) of RDB1815 and RDB1816
To determine the half-life of two IL-1Ra mucin fusion polypeptide constructs: RDB1815 and RDB1816, pharmacokinetic studies were performed in rats. In n = 3 rats per dose group, a single dose of RDB1815 was delivered subcutaneously (5.6 mg / Kg) or intravenously (2.1 mg / Kg), and a single dose of RDB1816 was subcutaneously (6.4 mg / Kg) or intravenously (2.4 mg / Kg). Blood was collected at various time points over 6 days and analyzed for IL-1Ra by ELISA.
薬物動態学的データ(図17)から、RDB1815およびRDB1816の半減期は、IVによる場合にはそれぞれ17.9hおよび13.9hと計算され、SCによる送達の場合にはそれぞれ11.0hおよび8.0hと計算された。これは、未修飾のIL−1Ra対照(アナキンラ)について報告された値を上回る10倍〜14倍の半減期の延長を示す。その結果、RDB1815およびRDB1816の両方の暴露は、著しく増加し、マウスCAIAモデルにおいて観察された有効性と一致する。 From the pharmacokinetic data (FIG. 17), the half-lives of RDB1815 and RDB1816 are calculated as 17.9 h and 13.9 h, respectively, by IV, and 11.0 h and 8. Calculated as 0 h. This represents a 10 to 14 fold increase in half-life over that reported for the unmodified IL-1Ra control (Anakinra). As a result, both RDB1815 and RDB1816 exposure increased significantly, consistent with the efficacy observed in the mouse CAIA model.
実施例7.ムチン−エキセンジン−4コンストラクトRDB2203の分子量
RDB2203を、SDS/PAGEおよびスーパーデックス200カラムでの分析用ゲル濾過を用いて特徴付けた。SDS/PAGEにより、RDB2203の見かけの分子量は約45kDであり、その計算されたポリペプチドの分子量22.8kDの約2倍であり、高レベルのグリコシル化と一致する(図18:左上の分子マーカー)。分析用ゲル濾過により、RDB2203の見かけの分子量は、高度にグリコシル化されたムチンドメインによって付与される巨大流体力学半径により、120kD(158kDと75kDの標準物質の間の単一ピーク)である(図19)。
Example 7 The molecular weight RDB2203 of mucin-exendin-4 construct RDB2203 was characterized using analytical gel filtration on SDS / PAGE and
実施例8.RDB2203の生物活性
GLP−1受容体をアゴナイズするRDB2203の能力を、DiscoveRx社のPathHunter eXpress GLP−1受容体cAMPアッセイを用いて測定した。このアッセイを、製造業者の指示に従って実行した。結果は、RDB2203がGLP−1受容体の強力なアゴニストであり、1.5nMのEC50を示し、これは未修飾のエキセンジン−4(0.07nMのEC50)よりも約21倍効力が低い(図20)。
Example 8 FIG. The ability of RDB2203 to agonize the biologically active GLP-1 receptor of RDB2203 was measured using the DiscoverHunt x PathHunter eXpress GLP-1 receptor cAMP assay. This assay was performed according to the manufacturer's instructions. The results show that RDB2203 is a potent agonist of the GLP-1 receptor and exhibits an EC 50 of 1.5 nM, which is about 21 times less potent than unmodified exendin-4 (0.07 nM EC 50 ). (FIG. 20).
実施例9.RDB2203の薬物動態プロファイル
ラットにおいて、RDB2203を0.65mg/kgで静脈内に、0.65mg/kgおよび7.0mg/kgで皮下に投与した。非ムチン化エキセンジン−4と比較して、RDB2203は、半減期の増加(2.0時間対0.5時間、iv)およびクリアランスの低下(74ml/時/kg対200ml/時/kg、iv)を示し、総暴露の増加をもたらした(1Ai,G.,et al.;Pharmacokinetics of exendin−4 in Wistar rats;Journal of Chinese Pharmaceutical Sciences;17(2008)6−10)(図21)。皮下経路を介して、RDB2203も、未修飾エキセンジン−4の65%と比較して、95%を超えるバイオアベイラビリティの向上を示した(図21)。
Example 9 RDB2203 Pharmacokinetic Profile In rats, RDB2203 was administered intravenously at 0.65 mg / kg and subcutaneously at 0.65 mg / kg and 7.0 mg / kg. Compared to non-mucinated exendin-4, RDB2203 increased half-life (2.0 hours vs. 0.5 hours, iv) and decreased clearance (74 ml / hour / kg vs. 200 ml / hour / kg, iv) ( 1 Ai, G., et al .; Pharmacokinetics of exendin-4 in Wistar rats; Journal of Chinese Pharmaceutical Sciences; 17 (2008) 6-10). Via the subcutaneous route, RDB2203 also showed greater than 95% bioavailability improvement compared to 65% of unmodified exendin-4 (FIG. 21).
本明細書で言及される特許および科学文献は、当業者に利用可能である知識を確立する。本明細書に引用される全ての米国特許および公開されたまたは未公開の米国特許出願は、参照により援用される。本明細書で引用される公開された全ての外国特許および特許出願は、参照により本明細書に援用される。本明細書で引用される公開された全ての他の参考文献、文書、原稿および科学文献は、参照により本明細書に援用される。 The patent and scientific literature referred to herein establishes the knowledge that is available to those skilled in the art. All US patents and published or unpublished US patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference.
本発明は、特にその好ましい実施形態を参照して示し、説明してきたが、添付の特許請求の範囲によって包含される本発明の範囲から逸脱することなく、形態および詳細における様々な変更がなされ得ることは当業者に理解されるであろう。また、本明細書に記載の実施形態は相互に排他的ではなく、様々な実施形態の特徴は、本発明に従って全体的にまたは部分的に組み合わせることができることも理解されたい。 Although the invention has been particularly shown and described with reference to preferred embodiments thereof, various changes in form and detail may be made without departing from the scope of the invention as encompassed by the appended claims. This will be understood by those skilled in the art. It should also be understood that the embodiments described herein are not mutually exclusive, and the features of the various embodiments may be combined in whole or in part according to the present invention.
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